Several countries around the world have implemented multicomponent interventions to enhance primary care, as a way of strengthening their health systems to cope with an aging chronically ill population and rising costs. Some of these efforts have included technology-based enhancements as one of the features to support the overall intervention, but their details and impacts have not been explored.This study aimed to identify the role of digital/health technologies within wider multifeature interventions that are aimed at enhancing primary care, and to describe their aims and stakeholders, types of technologies used, and potential impacts.A systematic review was performed following Cochrane guidelines. An electronic search, conducted on May 30, 2019, was supplemented with manual and grey literature searches in December 2019, to identify multicomponent interventions that included at least one technology-based enhancement. After title/abstract and full text screening, selected articles were assessed for quality based on their study design. A descriptive narrative synthesis was used for analysis and presentation of the results.Of 37 articles, 14 (38%) described the inclusion of a technology-based innovation as part of their multicomponent interventions to enhance primary care. The most commonly identified technologies were the use of electronic health records, data monitoring technologies, and online portals with messaging platforms. The most common aim of these technologies was to improve continuity of care and comprehensiveness, which resulted in increased patient satisfaction, increased primary care visits compared to specialist visits, and the provision of more health prevention education and improved prescribing practices. Technologies seem also to increase costs and utilization for some parameters, such as increased consultation costs and increased number of drugs prescribed.Technologies and digital health have not played a major role within comprehensive innovation efforts aimed at enhancing primary care, reflecting that these technologies have not yet reached maturity or wider acceptance as a means for improving primary care. Stronger policy and financial support, and advocacy of key stakeholders are needed to encourage the introduction of efficient technological innovations, which are backed by evidence-based research, so that digital technologies can fulfill the promise of supporting strong sustainable primary care. Primary care is often considered a cornerstone of health care systems. Health systems with strong primary health care produce better and more equitable health outcomes, are more efficient, and can achieve higher user satisfaction in comparison to health systems with only a weak primary care orientation ,2. ChangMany countries have implemented a wide array of innovations to enhance primary care, ranging from policy initiatives, such as capitated reimbursement, to ground level improvements, such as improving access to primary care practices and enhancing the roles of nurses to provide comprehensive primary care services -8. As inThere have been many studies emphasizing individual digital technologies for improving specific aspects of health care and primary care. Some of these include digital health assistants to help with administrative tasks, medical chatbots to engage patients more frequently, and the use of electronic health records and telemedicine, among others -11. HoweWe aimed to systematically explore the role that health/digital technologies have played in multicomponent efforts designed to improve primary care by identifying (1) the types of technologies implemented, (2) the functional objective of the technology, (3) the relevant stakeholders, and (4) whether they have an impact on enhancing the defining features of primary care  , denotedMulticomponent interventions/innovation environments: programs or strategies composed of several innovations/features to enhance primary care.Innovation features: individual innovation elements included in multicomponent interventions.Health technologies: application of scientific knowledge to solve health care–related problems, including its corresponding machinery and equipment .4Cs: the primary care core functions .Quadruple aim outcomes: the four types of outcomes to measure successful health system improvements .A systematic review was designed and performed following Cochrane guidelines for conducting systematic reviews . The detthe paper stamp checklist tool enhances asthma guideline knowledge and implementation by primary care physicians), and based on this, we determined that consideration of studies describing interventions with at least three distinct innovation features and measuring at least five outcome measures could ensure that the interventions were indeed “multicomponent.”An electronic database search was performed in order to identify (1) multicomponent interventions or “innovation environments” aimed at enhancing primary care (with at least three innovation features); (2) factors influencing at least one of the primary care core functions (4Cs), and (3) studies reporting on any of the four basic types of outcomes of a successful health system   and provA search strategy was developed, and it focused on the following three main sets of terms: (1) primary care–related terms; (2) innovation/reform/enhancement-related terms; and (3) study design filters . The eleWe defined health technologies, using definitions from two World Health Organization reports, as the “application of scientific knowledge for practical purposes, including its corresponding machinery and equipment, to solve health care–related problems and improve quality of life”  and encoQuality evaluation of the included studies was based on study design, using the National Institutes of Health–National Health, Lung and Blood Institute’s “Study Quality Assessment Tools” , a comprAfter the electronic search, subjecting the articles to the inclusion/exclusion criteria and manual reference and grey literature searches resulted in 37 articles fulfilling the requirements for multicomponent interventions as described above. From these, 14 studies had technology-based enhancements and were included in the analysis .Articles were published between 2008 and 2017, and half of them were published since 2016. Most described studies performed in the United States . Additionally, four were from Europe (two from Germany and two from Spain) and one was from Argentina. Eight articles mentioned policies influencing the implementation of the innovation programs as broader country, regional, or organizational efforts to enhance primary care  22-35].-35.22-35In terms of study designs and quality evaluation results, three publications reported controlled interventions , six reported observational cohort or cross-sectional studies with controls , one reported a case-control study of “fair” quality, and four reported pre-post studies without controls . Populations studied or linked to the results included the general population enrolled in the programs (in six articles), chronically ill patients with one disease or complex chronic patients (in four articles), and special populations, including elderly and disadvantaged populations (in four articles).The interventions in the articles included between four and 11 “innovation features”  describing multicomponent interventions to enhance primary care included technology-based enhancements as one of the innovation elements  22-35].-35.22-35According to the descriptions of the articles, we were able to identify the following six broad categories for the types of implemented technologies (description below includes intended stakeholder and use):electronic medical/health records [1. Enhancements leveraging  records ,24-28,34Data monitoring technologies/online registries [2. gistries ,26-29,34online portals and messaging platforms [3. Web-based latforms ,32,34,35Medication-specific eHealth/information technology tools [4. gy tools ,31: it wTelephone-based enhancements [5. ncements : it was Electronic consultations between providers [6. roviders : it was Based on the description of the technological enhancements included in the studies, we were able to link them to the 4Cs in the following way:First contact: Three programs aimed to apply technology to impact this feature through telephone-facilitated access to primary care colleagues, facilitated appointment scheduling through web portals, and updated digital health systems for easier patient access.1. Comprehensiveness: Six interventions sought to increase the ability to manage a wider range of problems with technology, including providing additional health promotion information through patients’ web portals and enhancing capacity for providers to better use electronic medical records, improve medication prescription, and provide improved preventive and chronic care.2. Coordination: Three programs used technology to improve care coordination by improving EHR-enabled information exchange and by allowing electronic consultations to facilitate care among primary care providers and specialists.3. Continuity: Nine interventions sought to enhance the longitudinal relationship between patients and providers by enhancing the identification and follow-up of patients for individualized care, allowing more comprehensive identification and monitoring of service needs, and improving communication between patients and providers via online messaging or telephone contact.4. Since these technology-based innovation elements are part of wider innovation environments, which include additional enhancement features, it was not possible to attribute outcomes specifically to the identified technologies. However, we still present the outcomes of the full innovation environments in an effort to elucidate the potential role of these technologies in the outcomes. The numerical magnitudes for each outcome are presented in health care costs and utilization, increased cost saving and decreased costs for some parameters  patient satisfaction, increased satisfaction with timely appointments and self-management support and increased satisfaction with the ability to see the usual doctor; (4) provider satisfaction, improved perception toward place of work’s quality and services provided, and its consideration as a good place to work.Overall, the studies presented mixed results  for all types of outcomes, except for provider satisfaction, which was reported only in one study. The most consistent improvements per type of outcome were as follows: (1) er month  and druger month ) and inchealth care costs and utilization, nonsignificant changes or simultaneous improvements and deteriorations depending on the study for hospital admissions, readmissions, and emergency department visits; (2) population health outcomes, nonsignificant changes for cholesterol and lipid levels, myocardial infarction, and stroke; (3) patient satisfaction, no differences for communication with providers and for primary care provider performance.The most consistent mixed results by the type of outcome were as follows: (1) The most consistent deteriorations were found for some health care costs and utilization outcomes, such as increased number of prescriptions, increased costs for general practitioner  and specialist (intervention €22 more expensive than control per patient) consultations , and incOnly 38% of our identified multicomponent interventions that aimed at enhancing primary care included technology-based enhancements, highlighting the fact that technology has not played a major role in comprehensive efforts aimed at enhancing primary care. This is not surprising, as it has been widely acknowledged that innovation in health care has always been difficult , especiaMost of the included articles reported on health care costs and utilization outcomes, signaling that technology-based efforts are either aimed at decreasing costs and utilization or at least not increasing costs without contributing to other aspects of system success. In fact, the only considerable unintended consequences were increased costs for general practitioner and specialist visits, and increased costs of prescription coverage (in some studies), suggesting that introducing technologies in health care can lead to increased costs, as it has been consistently reported in the literature -42.The most common technology identified within these efforts was EHR, which is also not surprising given the widespread advocacy for this technology ,44, and When analyzing the interventions in terms of their impact on the 4Cs, the technologies implemented were mostly aimed at improving continuity by increasing the identification and follow-up of patients (with labels in EHRs and telephone communication), enhancing monitoring efforts for identifying care and service needs , and ensuring more constant communication between providers and patients via online messaging. This reflects the growing importance of continuity of care, which in the past has had weak evidence linked to its benefits, but was recently highlighted as important, especially with regard to its link to decreased mortality risk ,47. TechIn terms of outcomes, the literature provides limited but useful information. For example, increased patient satisfaction with timeliness of care, scheduling, and better self-management support could be in part explained by the use of online patient portals. Such portals allow patients to schedule appointments, see their own medical records, and access additional prevention information. Increased primary care visits, relative to specialist visits, appear to result from innovations that enhance monitoring of services needed and follow-up of patients (identified through EHRs and/or by telephone follow-up). The introduction of medication-specific digital/information technology tools could be associated with differing impacts. While studies reported a decrease in the costs of drug prescriptions and medication therapies, they also reported an increase in the mean number of drugs prescribed, and it was also associated with more costly consultations (around €25 extra per consultation ).In order for digital technologies to play a more prominent role in primary care enhancement efforts, there is first a need for a responsible policy to support their development and introduction . For exaThere are some limitations for this study. The nature of the search and the specific requirements for including studies  may have made us overlook other important technological innovations aimed at improving primary care that had qualitative assessments only or did not measure quadruple aim outcomes. Similarly, since this review only focused on published and grey literature, it did not account for quality improvement interventions implemented at, for example, private primary care or accountable care organizations, which may have included technological innovations but no published results. Therefore, although technology may have a more prominent role in primary care–enhancing initiatives overall, the results from published and grey literature do not indicate so. Additionally, the fact that technological enhancements were one of many components within a primary care enhancement effort, our study eligibility criteria did not allow us to establish the actual and specific impact of the technologies on outcomes. However, it did help to situate these technologies within multicomponent innovation strategies and to gain preliminary insights into how technological enhancements may support other nontechnologically based innovation features and their impacts on the four primary care functions.Taking all of this into account, future research should try to pinpoint the specific impact of technology-based innovation features within wider efforts aimed at enhancing primary care. This would mean including specific measures that could link outcomes to the use of such technology and quantify this impact. This exercise would also help to identify which of the 4Cs of primary care is being impacted by this technology, which would help understand the mechanisms of how these innovations are improving care. An additionally interesting research direction would be to explore how technological innovations are being leveraged at primary care private practices and/or accountable care organizations, to understand the actual role of technology in quality improvement initiatives for which there is no publicly available data. Such research could provide a more balanced view of the actual usage of technological innovations in primary care at the ground level.Although technology and digital health have been proposed and encouraged as possible solutions to improve primary care, they have not played a major role in formally evaluated multicomponent interventions aimed at enhancing primary care, as reflected in the published and grey literature. Other types of nontechnologically based innovations, such as those aimed at improving access, restructuring payments for providers, and providing team-based care, have been much more widely implemented, reflecting that digital health technologies have not yet reached maturity or wider acceptance as a means for improving primary care. Leveraging technologies already in use, such as EHRs, and internet-based technologies, such as online patient portals, seems to provide promising avenues to improve continuity and comprehensiveness in primary care, which may eventually lead to better health outcomes and improved patient satisfaction. A stronger push is needed if technologies are meant to support wider efforts aimed at enhancing primary care and for them to play a more substantial role within these efforts. High-level policy and financial support must be designed to focus on the needs of a diversity of stakeholders and to encourage evidence-based research based on a coherent set of methods and measures. In this way, we can hope to fulfill the promise of technologies and digital health to enhance health care through strong sustainable primary care.


Advance Care Planning (ACP) is a process that supports individual’s understanding and sharing of personal values, life goals, and preferences regarding future medical care, so that they obtain care consistent with these during serious and chronic illness. While ACP is important for all, it is especially so for people who fall outside traditional, western, heteronormative contexts . This symposium draws from research conducted by the Diversity Access Team [part of a national project iCAN-ACP Improving Advance Care Planning for Frail Elderly Canadians]. The first paper presents results from focus groups conducted with loved ones of South Asian, Chinese and Lesbian, Gay, Bisexual, and Transgender (LGBT) older adults living in care homes; issues identified as barriers include starting ACP conversations too late (“my husband has severe dementia”), lack of consideration of cultural traditions and, in the case of LGBT older adults, their non-family support networks. The second paper draws from focus groups with care home staff, implicating their own training as a barrier to assisting residents/families with ACP as well as resident, family, institutional and cultural influences. A third paper reports on an educational intervention designed to increase staff understanding of ACP and comfort in assisting residents/families with ACP. The fourth paper reports feedback received on two ACP planning tools, reflecting the importance of minority group representation in visuals and text. Together, these papers underscore the importance of taking culture into consideration in framing and discussions of fostering ACP among minority populations.


In studies of community-based health behavior interventions  one goal in analysis is to show expected relationships between measures of intervention and clinically relevant outcomes. Many programs fail to show such clear links for many reasons beyond lack of intervention effectiveness. These secondary analyses were undertaken to assess if the measurement properties (stability and responsiveness) of intervention measures could have contributed to study findings. A feasibility study of lifestyle treatment of metabolic syndrome  had achieved 19% reversal over one year, yet neither diet quality nor fitness were associated with cardiovascular disease risk. Confirmatory factor analysis was used to examine fit of measurement models and factorial invariance was tested across three time points , gender , and disease status (diabetes) for the Healthy Eating Index (HEI) (Canada 2005) and several fitness measures . The model fit for HEI was poor and could account for the lack of association seen in the original study. More development of diet quality measures is needed. The model for fitness, however, demonstrated excellent fit and displayed measurement equivalence across time, gender, and disease state. A higher degree of confidence exists when measurement equivalence/invariance is demonstrated, allowing for reliable tests of differences in comparison groups. The use of a multiple measure of fitness, including cardiorespiratory fitness, flexibility, and strength, helps eliminate limitations of using measures from a single domain or self-reported data is promising and should be considered in future work.


Supplemental Digital Content is available in the text. In most cases, tinnitus is accompanied by some degree of hearing loss. Current tinnitus management guidelines recognize the importance of addressing hearing difficulties, with hearing aids being a common option. Sound therapy is the preferred mode of audiological tinnitus management in many countries, including in the United Kingdom. Combination instruments provide a further option for those with an aidable hearing loss, as they combine amplification with a sound generation option. The aims of this scoping review were to catalog the existing body of evidence on combined amplification and sound generation for tinnitus and consider opportunities for further research or evidence synthesis.A scoping review is a rigorous way to identify and review an established body of knowledge in the field for suggestive but not definitive findings and gaps in current knowledge. A wide variety of databases were used to ensure that all relevant records within the scope of this review were captured, including gray literature, conference proceedings, dissertations and theses, and peer-reviewed articles. Data were gathered using scoping review methodology and consisted of the following steps: (1) identifying potentially relevant records; (2) selecting relevant records; (3) extracting data; and (4) collating, summarizing, and reporting results.Searches using 20 different databases covered peer-reviewed and gray literature and returned 5959 records. After exclusion of duplicates and works that were out of scope, 89 records remained for further analysis. A large number of records identified varied considerably in methodology, applied management programs, and type of devices. There were significant differences in practice between different countries and clinics regarding candidature and fitting of combination aids, partly driven by the application of different management programs.Further studies on the use and effects of combined amplification and sound generation for tinnitus are indicated, including further efficacy studies, evidence synthesis, development of guidelines, and recommended procedures that are based on existing knowledge, expert knowledge, and clinical service evaluations. In most cases, tinnitus is accompanied by some degree of hearing loss . CurrentHistorically, sound was used to mask tinnitus, that is, reduce tinnitus loudness or make tinnitus inaudible . In receThe aim of the scoping review was to map relevant literature in the topic of interest . This tySecondary aims of the review were to describe (1) the literature where combined amplification and sound generation were used as part of a treatment program, and (2) where research gaps (opportunities for research) or large bodies of evidence already existed (opportunities for evidence synthesis).We followed Clinicaltrials.gov, www.who.int/trialsearch, Google Scholar, China National Knowledge Infrastructure (CNKI), International Standard Randomized Controlled Trial Number (ISRCTN), International Clinical Trials Registry Platform (IC-TRP), DART Europe (UK and European), ProQuest Dissertations and Theses (US), Cos Conference Papers, Google Scholar, Institute of Electrical and Electronics Engineers and Institution of Engineering and Technology (IEEE/IET) Electronic Library, Scopus, Web of Science, Zetoc, Open Gray. Gray literature records were included if the full text was accessible . Manual searches of key hearing aid manufacturers’ websites were performed to look for further journal publications. A hand search of reference lists from included articles was performed after final inclusion, last updated in May 2017.A wide variety of databases were used to ensure that all relevant records within the scope of this review were captured. This included gray literature, conference proceedings, dissertations and theses, as well as peer-reviewed journal articles. Search engines used were MEDLINE, Web of Science, The Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), Latin American and Caribbean Health Sciences Literature (LILACS), KoreaMed, IndMed, PakMediNet, CAB Abstracts, The search strategy applied to each search engine is reported in Figure The search of Google Scholar returned many thousands of records. Therefore, as this particular search engine arranges the results by relevance, all records were included up to the point when there were no more relevant records identified on three consecutive pages of 10 records. Three hundred records (corresponding to the first 30 pages) were carried forward for title/abstract screening. These search strategies returned 5959 records altogether.The records were included if they involved combined amplification (combination aids or wireless streaming) as a treatment option. Duplicate (n = 3182) records were removed. The next step considered title and abstracts, and a further 2618 records were judged to be out of scope and were excluded. All excluded records involved forms of therapy that were not combined amplification and sound generation.Record screening was completed independently by two authors to avoid any bias . Two autA further 90 records were deemed out of scope, and two records did not provide meaningful data to be extracted. Therefore, from the 171 records, a further 92 records were excluded, leaving 79. A further 10 records were identified in update searches, giving a total of 89 records, which were retained for data extraction.A template for data extraction was created and agreed by two authors. The data extraction form was piloted using two records that were excluded as they regarded another type of intervention (not combined amplification and sound generation). Data extracted were type of technology used (combination aids of wireless streaming), type of study , context, research question, main findings, additional results relevant to the review questions, general characteristics of the records , manufacturer; peer-review (yes/no), study design , subject population, number of subjects contributing data, power analysis (yes/no), funding to account for any potential bias, and outcome measures; type of sound used, management program , candidacy, fitting, instructions to patients.Two authors conducted data extraction independently. A meeting between the two authors was organized to resolve any discrepancies and agree on a final data set. Most discrepancies involved one or other author identifying additional information relevant to the data items of interest, for example, a potentially relevant detail spotted in a line of discussion that was not identified or extracted by the other author. Where these discrepancies in the extracted data were present, authors referred to the original record and agreed a final selection of data through discussion.To provide a structure for subsequent content analysis and narrative review, records were categorized according to whether combination hearing aids were used as a primary treatment or were used as part of a treatment program or package. There was a possibility to assign the same record to more than one category if authors decided that one would not reflect the content adequately. Thematic analysis was conducted to describe the main findings of the records grouped in broad themes.The majority of records within scope of the research question comprised literature reviews, guides, or practice/concept descriptions (n = 48), followed by investigational studies (n = 38). Furthermore, the majority of records were published in peer-reviewed journals (n = 64). Eighty-three records regarded combination hearing aids, while only six records regarded wireless streaming. Methodology for investigational studies varied considerably with a majority of uncontrolled before-and-after studies. Altogether, 35 investigational studies applied the prospective design. Sample size varied from one to 1888, with only one study  basing sOne potential source of bias was whether full or part funding for the study or devices was provided by manufacturers of hearing aids, or where there were authors who were employed by the manufacturer of investigated devices. Such conflict of interest was reported in 17 included records.The distribution of records over time reflected the introduction into clinical practice and recent increased use of combination hearing aids as a management option, a trend likely related to the improved quality of amplification provided by the instruments. Records came from the United States (n = 48), followed by the United Kingdom (n = 16), Germany (n = 5), Brazil (n = 3), Italy (n = 3), and Australia, China, Denmark, France, Greece, Japan, Mexico, Spain, Switzerland, Turkey, and New Zealand  followed by Visual/Numeric Analog Scales . Among the tinnitus-specific questionnaires used, the most common were Tinnitus Handicap Inventory , Tinnitus Functional Index (n = 7), and Tinnitus Handicap Questionnaire  showed a large variability in the study design, with uncontrolled before-and-after design being the most common (n = 11), followed by randomized or quasi-randomized trials (n = 8) and crossover studies (n = 3). Other study designs included historically controlled trial (n = 1), nonrandomized controlled study (n = 1), case reports (n = 2), a pilot study (n = 1) and a survey of clinicians (n = 1). There were 24 reviews in this category, of which four were systematic reviews including one Cochrane review  , two proRecords that described combination aids as a management option but did not report investigative studies were literature reviews (n = 15), practice guides (n = 4), concept/product descriptions (n = 3), and a patient survey exploring their characteristics (n = 1). The records often briefly mentioned combination aids as a management option without providing any further details. Most of these records provided recommendations regarding candidacy for combination aids, with some records providing more detail on available noise options and fitting recommendations. Two records described wireless streaming as a flexible option that addressed the needs of different tinnitus management plans .Two records focused on candidacy and choice of devices, including combination aids for tinnitus. One record investigated patient satisfaction with Widex Clear hearing aids , concludCombination aids would be offered in principle to those who have tinnitus and co-existing hearing loss, with several studies indicating clinically significant, bothersome, or debilitating tinnitus as an additional criterion . Some auTM permits use of any sound that provides maximum masking benefit ; therefoWireless streaming allows any sound to be transmitted through to the hearing aids. In the included records that did not follow the TM approach, the level of noise was advised to be set at the mixing point , nonrandomized controlled studies (n = 4), randomized or quasi-randomized trials (n = 3), a crossover pilot (n = 1), a clinician survey on the use of Zen for tinnitus (n = 1), and a retrospective uncontrolled before-and-after study (n = 1). The other records were literature reviews (n = 16), practice guide/description (n = 5), and concept/product descriptions (n = 2).Thirty-eight records described combined amplification and sound generation as a part of a multicomponent treatment, including Tinnitus Retraining Therapy , Widex Zen Therapy (n = 7), drugs and instrumentation (n = 2), Progressive Tinnitus Management , Tinnitus Activities Treatment , and multidisciplinary tinnitus management (n = 1). See Table 2, Supplemental Digital Content 2, Recommendations on candidacy and fitting of combination hearing aids strongly depended on the management program followed. There were also marked differences in approaches between different management programs including fitting laterality and recommended daily use.In principle, all programs advised the use of combination aids for people who have tinnitus and co-existing hearing loss. However, the candidacy decisions were based on different criteria in each of the programs. For example, within TRT, ear-level devices were recommended for TRT Category 2 patients (severe tinnitus and significant subjective hearing problems). Combination aids were a preferred option, with hearing aids only recommended in cases where cost was an issue or the specifics of hearing loss did not allow for fitting of combination aids . In TRT,In Zen Therapy, counseling and relaxation play a crucial role in tinnitus management, and combination aids were recommended for anyone with tinnitus as a main complaint and hearing loss . SimilarSimilar to TRT, TAT addressed the reaction to tinnitus and uses informational counseling, activities engagement, sound therapy . In thisPTM is a five-level approach to management of patient with tinnitus consisting (1) screening for clinically significant tinnitus; (2) group education; (3) intake assessment; (4) application of treatment program if further treatment necessary; and (5) extension and broadening of treatment if results not satisfactory . Within Goldstein and Shulman (2010) describe Tinnitus Targeted Therapy as a combined treatment of medication and instrumentation focusing on pharmacotherapy that evolved from authors’ clinical experience. Instrumentation was recommended to 10%–15% of tinnitus patients resistant to pharmacotherapeutic modalities for tinnitus relief. Different types of instruments could be recommended, including combination hearing aids for people with mixed or sensorineural hearing loss and tinnitus. Currently, there are 2 RCTs registered that used combination hearing aids as an intervention Table . AdditioThis scoping review was undertaken to establish what information was available from the existing literature and identify any gaps and opportunities in the current body of knowledge regarding combined amplification and sound generation for tinnitus.Over the years, the number of studies looking at the combined amplification and sound generation for tinnitus increased, reflecting the increased popularity of this management option in clinical practice. Combination aids were used as a part of many different management programs  and outside of those.There was a rich literature describing the principles of various management programs and providing guidelines on different aspects of tinnitus management within those programs, with many having strict criteria regarding candidacy, fitting, and use of combined amplification and sound generation by the patient. Most programs  did not specifically recommend the use of certain type of device such as combination hearing aid but suggest that positive results could be achieved using sound therapy in general, regardless of the mode of delivery. All of the above programs consisted of various components from which each was postulated to play an important role in the management of tinnitus. Practices were highly variable, however, with different management programs followed by different clinics.Most records seemed to support the use of combination hearing aids in tinnitus therapy, reporting improvements in tinnitus distress and handicap. Those results were achieved regardless of the management program followed as studies using sound therapy as a part of different programs reported positive results. Moreover, the small number of studies that directly compared different programs or approaches suggested that each of those could provide a reduction in tinnitus distress .Although a large number of records was found (n = 89), only 10 compared combined amplification and sound generation for tinnitus to amplification only. Most studies (n = 7) found no difference in tinnitus distress or handicap between amplification only and combination aids. However, the picture was not clear as only two of those studies were RCTs published in peer-reviewed journals . Both RCCurrent combination aids offered a wide choice of different noise options , 2014. WAlthough several studies mentioned patients’ preferences as an important factor in choosing certain type of devices for tinnitus therapy, preferences for different type of sounds and their acceptability were rarely investigated. In fact, acceptability and preferences regarding different sound options available within combination hearing aids were investigated only in the context of using different fractal tones within the Zen therapy . This waGiven that most records described combined amplification and sound generation in the context of larger management program, combining multiple approaches to manage tinnitus, it was often difficult or even not possible to draw conclusions specific to that component of the program. It is, therefore, possible that other components, rather than the devices, might have played a role in the observed improvements in tinnitus distress or handicap. For example, Marked variability was observed in candidacy and fitting of combination aids between different management programs and different studies. It was not clear, however, if any of those approaches yielded better results. Not many studies directly compared different management programs. While p < 0.05). Further studies investigating the role of different noise settings within combination aids in achieving long-term relief from tinnitus are needed.One of the main differences between management programs related to the level of the noise used in the tinnitus therapy. While TM aims to provide immediate relief from tinnitus, achieved by complete masking if possible without setting the masking sound to an uncomfortable level , other aOnly six records described wireless streaming as a management option for tinnitus, and only one study compared the efficacy of this option as compared to built-in sound generators. As streaming is a relatively new concept, further studies of its use in clinical practice, acceptability, and efficacy must be completed.There are clearly many opportunities for further research in this field. Marked differences in clinical practice identified in this review pose a challenge for investigators devising protocols sufficiently flexible to address different patient groups, device options, and related practices. Assessments of patient subgroups for whom protocols should remain flexible versus those assessments of protocols requiring strict evaluation criteria will require justification and thorough understanding of current clinical practice. This could be achieved by country-wide service evaluation and seeking consensus between clinicians  regarding candidacy and fitting of combination hearing aids. Qualitative and quantitative data should be collected regarding the utilization of different options on the devices in the real world, acceptability of different noise options, and patients’ preferences. The above issues call for more pragmatic trial design.To make evidence synthesis worthwhile, one has to assure a sufficient number of eligible records exist. Applying the most common inclusion criteria for many systematic reviews, namely that studies need to be prospective studies published in peer-reviewed journals, 8 potentially eligible studies were identified in the included records. From those, 5 studies investigated the efficacy of combination hearing aids for tinnitus and 3 investigated sound therapy using different types of devices . Although data specific to combination aids were not available in the published version of those 3 records, the original data set could be requested from the authors, as is common practice when conducting systematic reviews.Variability in outcome measures used in clinical trials assessing clinical efficacy of treatment for tinnitus is a recognized problem, and efforts to create core outcome set in tinnitus to be used in clinical trials worldwide are ongoing. A review by No peer-reviewed studies investigating efficacy of wireless streaming were identified.The current review cataloged existing knowledge and knowledge gaps and opportunities around combined amplification and sound generation for tinnitus. A large number of records identified varied considerably in methodology, applied management programs, and type of devices. To inform evidence-based practice, further studies looking at efficacy , practice  acceptability, and preferences  should be conducted.This report is independent research by the National Institute for Health Research Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health.


The recognised relationship between oral health and general health, the rapidly increasing older population worldwide, and changes in the type of oral health care older people require have raised concerns for policymakers and health professionals. Nurses play a leading role in holistic and interprofessional care that supports health and ageing. It is essential to understand their preparation for providing oral health care.Objective: To synthesise the evidence on nursing students’ attitudes towards, and knowledge of, oral healthcare, with a view to determining whether oral health education should be incorporated in nursing education.Data sources: Three electronic databases - PubMed, Scopus, and CINAHL.Study eligibility criteria, participants and interventions: Original studies addressing the research objective, written in English, published between 2008 and 2019, including students and educators in undergraduate nursing programs as participants, and conducted in Organisation of Economic Co-operation and Development countries.Study appraisal and synthesis methods: Data extracted from identified studies were thematically analysed, and quality assessment was done using the Mixed Methods Appraisal Tool.From a pool of 567 articles, 11 met the eligibility criteria. Findings documented five important themes: 1.) nursing students’ limited oral health knowledge; 2.) their varying attitudes towards providing oral health care; 3.) the need for further oral health education in nursing curricula; 4.) available learning resources to promote oral health; and 5.) the value of an interprofessional education approach to promote oral health care in nursing programs.Limitations: The identified studies recruited small samples, used self-report questionnaires and were conducted primarily in the United States.The adoption of an interprofessional education approach with a focus on providing effective oral health care, particularly for older people, needs to be integrated into regular nursing education, and practice. This may increase the interest and skills of nursing students in providing oral health care. However, more rigorous studies are required to confirm this. Nursing graduates skilled in providing oral health care and interprofessional practice have the potential to improve the oral and general health of older people. Oral health is measured by the absence of orofacial pain, oral infection, periodontal (gum) diseases, tooth decay, tooth loss, and other orofacial diseases and disorders that can affect a person’s overall physical and mental health, and social well-being –3. This Worldwide, the oral health of older people, defined as those over 65 years of age, is poor with a high prevalence of dental caries, periodontal diseases, dry mouth problems, and incremental tooth loss . There iMost oral health problems experienced by older people are preventable or treatable . HoweverThe provision of quality and timely oral health care services to the rapidly increasing older population has become a large challenge for policymakers and health professionals , 19, 20.Interprofessional education and collaborative practice have been recognised as a valuable approach to alleviate the global health workforce crisis and prepare a health workforce that will better respond to local health needs and ensure safe, holistic practice . The WorNurses provide care to older people in various settings such as hospitals, residential aged care, rehabilitation units, as well as in the community. Community nurses can educate and empower older people to take an active role in their oral care to prevent oral problems . Nurses To synthesise the evidence on nursing students’ attitudes towards, and knowledge of, oral health care, with a view to determining whether oral health education should be incorporated in nursing education. To our best knowledge, no previous study has summarised the literature on this topic.What do nursing students understand about oral health care?What are the attitudes of nursing students towards providing oral health care?Is there evidence of oral health education and training in nursing curricula?A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .Original studies addressing the research questions, written in English, published between 2008 and 2019, including students and educators in undergraduate nursing programs as participants, and conducted in Organisation of Economic Co-operation and Development (OECD) countries. The review excluded studies involving students from certificate nursing courses, graduate nursing programs, and midwives. Studies reported in conference proceedings, short communications, thesis, or book chapters were also excluded.Three electronic databases were searched: PubMed, Scopus, and CINAHL. Boolean operators with the following keywords and strategy were used:  AND (nursing students OR nurse students OR nurse undergraduates OR nurse educators) AND . A detailed example of the search strategy used for Scopus is outlined Fig. . This seAll original studies, including quantitative, qualitative, and mixed-method studies, were selected if they met the eligibility criteria. After an initial search and removing duplicates from the search list, titles and abstracts were independently screened by two authors  and the full texts of identified papers were then sought. Studies not fitting the eligibility criteria were excluded before the full text was reviewed. In cases of disagreement, two additional authors  were consulted to resolve any conflicts. Disagreements were resolved with consensus by referring back to the protocol. Research data were synthesised systematically, and the quality of the included studies was then evaluated.The data collection form was developed by two authors  referring to previous systematic reviews in the related field; data extraction was then performed independently by VB. The accuracy of the extracted data was verified by the second author (HH). Information collected from the identified articles for this systematic review included: country and setting, details of participants, objectives of the study, research design, description of the main findings related to the three research questions, and the reported limitations of each study Table .Table 1Extracted data were analysed thematically to produce a narrative description of the findings. While thematic synthesis is commonly used for qualitative research outcomes, it can be used for quantitative research outcomes when there is heterogeneity in measurements. Therefore, the process of thematic synthesis was chosen to narrate the findings of this review . The theA meta-analyses of the identified studies was not possible because of the small number of studies, participants, and heterogeneity.The quality assessment of the identified studies was done by two authors  using the Mixed Methods Appraisal Tool (MMAT) . All stuFrom a pool of 567 articles, 11 met the eligibility criteria Fig. . A largeThe main findings of the 11 identified studies were 1.) nursing students’ limited oral health knowledge; 2.) their varying attitudes towards providing oral health care; 3.) the need for further oral health education in nursing curricula; 4.) available learning resources to promote oral health; and 5.) the value of an interprofessional education (IPE) approach to promote oral health care in nursing programs. The results of the quality assessment of the identified papers are shown in Tables Only three studies , 43, 45 Three studies conducted in the US , Japan , and TurSeven of the 11 studies provided suggestions for including an oral health component in nursing curricula. Six of the seven studies , 50–52 fLewis et al.  evaluateAn interprofessional education (IPE) model in which nursing students work with, learn from, and contribute to the oral-systemic knowledge of dental and other allied health students has been found effective in improving understanding of nursing students towards their role in oral health care , 50–52. As a result of their IPE experiences in lectures and simulation exercises, nursing students showed significant improvement in oral health behaviour, knowledge, and attitudes regarding the importance of oral health care , 52. IntThis review of 11 identified studies documented limited oral health knowledge and varying attitudes (both favourable and unfavourable) of nursing students towards oral health care. The review identified available learning resources and highlighted the importance of an interprofessional education and practice approach in improving oral health knowledge and attitudes among nursing students.Growing evidence of the relationship between poor oral health and general systemic health requires urgent attention. The inclusion of oral health care education in nursing curricula, integrated with an interprofessional approach, will strengthen the capability and interest of future nurse practitioners to include evidence-based effective oral health care in routine nursing care. It is important to understand that “oral health care” can be interpreted differently by different health professionals . For nurwww.smilesforlifeoralhealth.com) [Older people are at particular risk for poor oral health. This review showed a significant gap in the current literature on nursing students’ knowledge of oral health care for older people and how this gap is best addressed through interprofessional education and practice. Interprofessional education and practice is one of the best ways to improve both nursing students’ awareness of the importance of oral health and their role in improving access to and providing oral health services , 57. IPElth.com) .Implementing IPE into nursing curricula requires thought, time, and careful planning to ensure that students from other health-related programs can participate , 63, 66.Effective oral health education must include clinical practice and ideally interprofessional clinical practice. The best way to translate oral health learning to practice is to shift from the traditional physical assessment approach that is Head, Eyes, Ears, Nose, Throat (HEENT) to the Head, Eyes, Ears, Nose, Oral cavity, and Throat (HEENOT) approach for the assessment, diagnosis, and treatment of oral-systemic health . The HEEThis systematic review is a valuable initial step in identifying the current knowledge and attitudes of nursing students towards providing oral health care and recognising factors to reinforce their interest in oral health care, particularly for older people . ResultsMost of the reviewed studies were conducted in the United States and had small sample sizes belonging to a single location; therefore, the results cannot be generalised. Some intervention studies had quasi-experimental designs, and there was a lack of blinding of the intervention leading to questions on the trustworthiness of the study results. Self-report questionnaires were used in the identified studies which may be biased by respondent beliefs. The long-term evaluation results of an integrated oral health learning model are still not available to check the effectiveness of IPE in building nursing students’ capacity in oral healthcare delivery.This review supports the need to integrate oral health education into nursing curricula, ideally through an IPE approach, to increase nursing students’ knowledge and ability to provide oral care, particularly to maintain the health of older people, and to interest students in providing effective oral care. There is a need to conduct rigorous well-designed studies about how best to achieve this and measure its success. A future nursing workforce with competence in oral health care will help to improve the oral health and quality of life of all people, especially those who are older and dependent on others for care.


Cancers arise from the accumulation of somatic genome mutations, which can be influenced by inherited genomic variants and external factors such as environmental or lifestyle-related exposure. Due to the heterogeneity of cancers, precise information about the genomic composition of germline and malignant tissues has to be correlated with morphological, clinical and extrinsic features to advance medical knowledge and treatment options. With global differences in cancer frequencies and disease types, geographic data is of importance to understand the interplay between genetic ancestry and environmental influence in cancer incidence, progression and treatment outcome. In this study, we analyzed the current landscape of oncogenomic screening publications for geographic information content and quality, to address underrepresented study populations and thereby to fill prominent gaps in our understanding of interactions between somatic variations, population genetics and environmental factors in oncogenesis. We conclude that while the use of proxy-derived geographic annotations can be useful for coarse-grained associations, the study of geo-correlated factors in cancer causation and progression will benefit from standardized geographic provenance annotations. Additionally, publication-derived geographic provenance data allowed us to highlight stark inequality in the geographies of cancer genome profiling, with a near lack of sizable studies from Africa and other large regions. Cancer is one of the top causes of mortality globally, and the understanding of its genesis and pathophysiological mechanisms remains one of the major challenges in life sciences. Although the past decades have witnessed major improvements in cancer diagnostics and therapeutics—partially driven by rapid advances in genomic screening techniques such as DNA array and sequencing technologies—the overall spectrum of genomic alterations in malignant transformation and progression remains poorly understood.As a multistep genomic disease, different factors influence the transformation of somatic cells into malignant clones. Whereas the majority of oncogenomic variants arise as mutations in the DNA of somatic cells and affect genes involved in proliferation, differentiation and control of apoptosis, inherited (‘germline’) genomic variants can predispose to specific malignancies , 2. As ewww.ncbi.nlm.nih.gov/geo/) or EBI’s ArrayExpress (www.ebi.ac.uk/microarray-as/aer/), an exploration of published cancer genome studies using a geographic approximation method could provide a general picture of study geographies, help to understand the utility of proxy data and provide arguments about structured ‘geodata’ annotations in biomedical research.Since highly variable cancer rates by ethnicity and geography have been observed for multiple cancer types , inclusiin vivo systems and has led to thousands of publications of original studies. The corpus of scientific literature related to cancer genome screening experiments, pre-selected through similarities in subject and general scope, offers an opportunity for the analysis of longitudinal directions and possible gaps in this specific field of biomedical research.Cancer genomics data collections—representing the results of data curated from scientific studies and primary data resources—are essential for advancing our understanding of molecular mechanisms and guiding the improvement of treatment protocols. Whole-genome profiling for structural and sequence variations has become an integral part of the molecular assessment of cancer samples and progenetix.org), originally established in 2001 [Progenetix is a publicly available cancer genome data resource  stu in 2001 , Progene in 2001 , 18) and in 2001 , 20) stuHere we present an overview of the global distribution of cancer studies based on the literature data collected for the Progenetix database, used as an example for a curated knowledge resource covering the corpus of publications in a defined research area and containing readily available geographic provenance information. We highlight the importance of geographic data  and aim for the improvement of standards and consensus in metadata annotation of relevant clinical and individual features which would help elucidate the multi-factorial nature of cancer through epidemiological and correlation studies.As result of the standard Progenetix literature curation process 3240 publications were collected and included in the Progenetix database. The publications, spanning the years 1993–2019, were retrieved from PubMed by combining keywords using boolean AND (intersection) or boolean OR (union) such as ( (‘whole genome sequencing’ OR WGS) OR (‘whole exome sequencing’ OR WES) OR (array AND genomic) OR (SNP AND array) OR ‘comparative genomic hybridization’ OR CGH OR aCGH) AND (cancer OR leukemia OR lymphoma). For each publication, the number of analyzed biosamples  was determined, separately for the main genome screening technologies . Geographic point coordinates were assigned to each set of samples using the address (city) of the first author of the associated publication, serving as a proxy for the samples’ origins. Point coordinates were obtained for each city name using the external geographic database GeoNames (www.geonames.org).sample specific data >experiment location >first author proxy, where available.In contrast to the publication collection of the Progenetix resource, individual genome profiling experiments are labeled after review of existing information from associated publications or repository information for their ‘best available’ geographic origin, using a precedence of For a randomly selected subset of 200 articles, the article contents were manually examined in order to identify any text describing the geographic origin of the samples or patients. These locations, if present, could then be compared to the city of the first authors’ institutions for each article in this subset.A kernel density raster was generated from the geographic point coordinates using the ArcGIS Kernel Density tool, using a search radius of 200 km and a cell size of 25 x 25 km, with each point weighted by the number of samples associated to that location. The final map shows a smoothed representation of the density of genome profiling experiments per square kilometer around the world.Author collaborations were visualized at the country level using a set of 3093 publications from the Progenetix database where author affiliation countries could be automatically determined. Author affiliations were extracted by running the CERMINE tool  over thecountry counts) and how many times pairs of countries appeared together on an article (collaboration counts). We generated a network graph representation of this data using the Gephi visualization software [The set of affiliation countries (provided as country codes) was then extracted from these XML files for each article. We counted how many times a country appeared at least once in an article  and 28.0% contained indirect sample location information . The remaining 41.5% of the articles had no sample location information.Regarding the agreement between sample locations and first author locations, for the 117 articles that contained sample location, 52.1% agreed on a city/province level, additional 22.2% on a country and 13.9% on a continent level. For the remainder of the articles (11.9%), the first author location or full author location list provided an incomplete or misleading picture of the sample/patient locations described in the text: 7.7% of the articles contained samples from more than one continent and in 4.2% of the articles the sample location was in a different continent to the first author location.In summary, author proxy information provided a reasonable assignment at a ‘population’ scale, with 74.3% of correct attribution to at least country level . Nevertheless, when the attribution of geographic sample provenance is extrapolated from article authorship, there is a risk of potential non-alignment of the studies’ place of execution and the origin of the study material at higher resolution.Figure Figure In Figure The top two most frequent country collaborations are between researchers from the US and Germany (collaborating on 122 publications) and from the US with the UK (95 collaborations), reflecting an alignment of overall country contribution frequencies and international collaborations. The US features in six of the next seven most common pairs, collaborating most often with Canada (79), Italy (60), Spain (60), the Netherlands (58), Japan (49) and France (49). Though no African countries are represented in the graph, seven of these countries appear in our data, but below the country count cut-off value (7), with Egypt appearing as an affiliation country on five publications, the most for the African continent.Geographic provenance data can be a powerful tool for genomic data stratification and exploration. However, as we have observed, projects are frequently highly collaborative, with international contributions seen in at least one third of the published studies based on the contributing authors’ affiliations. Therefore, the use of submission location as a proxy for the geolocation of the studies’ samples does not represent a rigorous procedure, but rather is an operational simplification. Correlating geographic—and population background-related—patient information with genomic characteristics calls for a more ambitious approach, for which standards for the geographic attribution of individuals, biosamples and technical procedures should be established.beacon-project.io) [One of the current initiatives to address challenges in the generation and—particularly—accessibility of genomic data in biomedical research and medical practice on an international scale is the Global Alliance for Genomics and Health (GA4GH) . A speciject.io) .www.ebi.ac.uk/ols/ontologies/hancestro/) could provide an additional qualifier for ancestry–environment stratification. If implemented throughout an international ecosystem of GA4GH stakeholders, such structured annotations will allow for diverse causative and co-relational studies with great impact on genotype/phenotype correlations and epidemiological knowledge.The responsible sharing of genomics and health-related data needs to be supported by well-designed data schemas and Application programming interfaces (API). For several of those schemas, the inclusion of geolocation parameters has been found beneficial for supporting an effective implementation of the derived protocols, e.g. for the attribution of the geographical origin of individuals and biosamples, as well as for technical provenance tracking and regulatory procedures. One model of the different domains for geolocation attribution is presented in Figure While the extension of metadata annotations with geographic provenance information will provide opportunities for better stratification of data especially in large-scale meta-analyses, possible risks of, e.g. easier re-identifications of individuals through combination of genomic and location data  has to bAside from GA4GH, another important initiative within life sciences aiming at the FAIRification of data  is biosBased on the data from 3240 articles curated for the Progenetix resource, our analysis delivers an overview of the geographic provenance ‘landscape’ of cancer genome profiling publications, specifically of those containing whole-genome profile from hybridization  and sequencing  experiments. When using the city of the first author’s institution as proxy, we can show prominent disparities for geographic sample origins on a (sub-)continental scale, with only very limited contributions from studies of African, Central Asian or South American origin. While this result could be biased through the incomplete registration of relevant studies or country-specific biases in the registration of such studies in PubMed, it corresponds to the ‘visibility’ of this research to the international research community.gcpm.globalonc.org), a project which aims to promote research projects and facilitate collaborations, where users can browse and search for projects, people and events displayed on a world map [Previous studies have analyzed collaborations in science using author affiliations to analyze the spatial aspects of research and their role , 29. Othorld map .Over the past years, large collaborative initiatives have emerged with the aim of defining the genome of different cancers. With over 88 contributing projects, the ICGC has mapped the structural aberrations of 26 major cancer types across 16 countries and the European Union. Furthermore, The Cancer Genome Atlas (TCGA), with an overview of 33 different cancers based on 11 315 cases, provides a rich collection of high-quality tumor samples. However, with respect to reflecting population and geographic heterogeneity, based on samples from 14 contributing countries, the representation of population diversity is nevertheless limited with a great majority of samples labeled as being from ‘white’ individuals (8186 samples) and other groups represented in much lower numbers—1325 ‘not reported’, 934 ‘black or African American’, 675 ‘Asian’, 27 ‘American Indian or Alaska native’ and 13 ‘native Hawaiian or other Pacific Islander’. The data from the respective TCGA publications has been included in our analysis.Numerous scientific studies have pointed out disparities in cancer incidence, prevalence and mortality based on geographic location and called for further study of the influence of different genetic backgrounds on cancer development , 32, 33.Even with existing geographic provenance, such information can only provide an approximation of a patients ancestry, with varying probability and specificity depending on regional patterns of migration and admixture. For (cancer) genome profiling data with accessible genotyping information , a recent approach of direct genetic inference allows for the assignment of population groups from shared genomic ancestry . While tCorrect attribution of the geographic origin of a patient can provide valuable information as a proxy for two general classes of factors with a known role in cancer development: (i) environmental and lifestyle factors with exposure related to local or regional geographic origin and (ii) ancestry-related variation in occurrence or frequency of genomic variants providing heritable contributions to cancer development. However, the lack of standards and deposition requirements for geographic metadata in genomic data repositories and as part of scientific publication procedures currently limits potential benefits of geographic attribution in cancer genome studies. While the use of proxy information (e.g. location of author or data submitter) can be valuable in geographic epistemology and for coarse-grained geographic associations, detailed studies on the impact of geo-correlated factors in cancer causation and progression could be enabled through precise annotation of geographic provenance using standardized protocols and data formats.In our study, we present a GA4GH-derived concept for the structured annotation of geographic provenance data that accommodates for different levels of data attribution in genome—and possibly other—profiling analyses, and demonstrate its implementation in our ‘Progenetix’ cancer genome profiling collection, for stratification of CNV datasets according to their large-granular geographic origin.While the limited availability of structured geographic provenance data severely restricts options for detailed associations between geographic data and genomic parameters in cancer meta-analyses, the use of author-based proxy data allows an estimation of the overall international study landscape in the field of cancer genomics. Here, our analysis of 3240 publications shows large inequalities, with the majority of studies being contributed from European, North American and East Asian groups or collaborations, and the near complete lack of accessible cancer genome profiling data from Africa and, to a lesser extent, central Asia and South America. The lack of ethnic diversity in the current data collections—reflected in these extreme global imbalances—highlights the need to properly address global disparities in cancer research to enable the study of the influence of genetic background on cancer development.


Despite increased prevention efforts, HIV remains the leading cause of death among adolescent girls and young women in South Africa. Although research indicates important determinants of HIV acquisition at the individual and interpersonal levels, structural-level stigma and discrimination continue to be critical barriers to reaching and retaining this key population for HIV prevention and sexual and reproductive health services. Innovative and multilevel interventions are needed that can address the intersectional structural and gender issues that young women face, including stigma, alcohol and drug use, gender-based violence, and other risk factors when seeking health services. Oral pre-exposure prophylaxis (PrEP) taken daily has been found to be an effective biomedical HIV prevention tool. Testing a comprehensive gender-focused biobehavioral HIV prevention intervention that is inclusive of social ecological determinants, such as stigma and discrimination reduction in clinics, is critical for reducing HIV among adolescent girls and young women.This project involves both a Community Collaborative Board and a Youth Advisory Board in helping to adapt the Young Women’s Health CoOp intervention and the Health Policy Project (HPP) Stigma and Discrimination (S&D) reduction training curriculum to the setting and population. This study uses a two-by-two factorial design with stratified randomization of 12 clinics, each with distinct catchment areas. The Young Women’s Health CoOp addresses substance use, sexual risk, violence prevention and sexual negotiation, condom demonstration, and problem solving with the following additions: knowledge of PrEP, the importance of PrEP adherence, and sexual and reproductive health. Adolescent girls and young women will be assessed with behavioral and biological measures at baseline, 3-, 6- and 9-month follow-up. The S&D reduction training is provided for all staff in the clinics randomized to this condition. Clinic staff will be surveyed at baseline, 4- and 8-month follow-up. We will recruit 900 AGYW from communities in the 12 clinic catchment areas.The study findings, if efficacious across the outcomes, will be incorporated into the gender-focused HIV prevention intervention toolkit and disseminated to inform multilevel prevention approaches.NCT04048551 (Recruiting). Registered: August 7, 2019 (Retrospectively registered).ClinicalTrials.gov. Identifier:  Despite important progress globally to reduce HIV incidence, adolescent girls and young women (AGYW) continue to be disproportionately at risk of HIV acquisition . In SoutResearch indicates important determinants of HIV acquisition at the individual and interpersonal levels. However, structural-level stigma and discrimination (S&D) continues to be a critical barrier to reaching and retaining this key population for HIV prevention and sexual and reproductive health (SRH) services –6. AGYW Intersectional stigma toward AGYW is the convergence of multiple stigmatized identities, such as age, health, gender, behavior, and socioeconomic status . BecauseGlobally, momentum is increasing to avert HIV infection among AGYW via the use of comprehensive strategies in the care continuum. The South African government acknowledges this need, as demonstrated by its involvement in the Determined, Resilient, Empowered, AIDS-free, Mentored and Safe (DREAMS) program, which aims to prevent HIV among vulnerable AGYW by empowering them through social asset building and by providing post-violence care, contraception through SRH services, and HIV prevention such as condoms and biomedical prevention such as PrEP .Oral PrEP, a combination of the antiretroviral (ARV) medications emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) taken daily, prevents HIV acquisition among individuals who are HIV-negative. It has been found to be effective among women in Africa , 22. It Because of an inability to negotiate condom use or mutual monogamy –27, manyThe Women’s Health CoOp (WHC), the original intervention, is an evidence-based woman-focused HIV prevention intervention grounded in empowerment and feminist theory to increase individual knowledge and skills to reduce substance use and increase personal power around HIV risk behaviors . The WHCPRevention, Empowering, and PRotEcting (PrEPARE) Project includes knowledge of PrEP, such as the importance of adherence and in-depth information on contraception and other SRH options. The added elements of PrEP and SRH material, along with assistance with accessing clinics for PrEP initiation and adherence and contraception, ensures that AGYW receive a more comprehensive HIV prevention program and SRH services.The Young Women’s Health CoOp (YWHC) was originally adapted from a U.S. adolescent project and subsequently fielded in South Africa for a younger generation of women at risk for HIV , 19, 40.Although the YWHC addresses the individual and interpersonal needs of AGYW who engage in risk behaviors, such as alcohol and drug use and condomless sex, it did not address the structural barriers, such as stigma and discrimination, that many AGYW face when accessing clinics for services. Consequently, the structural aim of this study addresses S&D-reduction training in clinics.The Health Policy Project (HPP) Health Facility HIV-Stigma and Discrimination reduction training curriculum addresses barriers that arise from S&D. The HPP curriculum is based on a decade of implementation experience in Africa, South and South-East Asia, and the Caribbean . It has To decrease structural S&D in clinics and increase AGYW’s agency to protect themselves, a multilevel strategy is needed. The present study seeks to determine whether implementing a multilevel, woman-focused intervention for PrEP readiness, uptake, and adherence among vulnerable AGYW in Tshwane, South Africa, that includes S&D reduction assessment and training in clinics, is a viable complement to South Africa’s National Strategic plan for HIV, which includes a focus on AGYW . It alsoThis project comprises three specific aims. Aim 1, which was completed during the study’s formative phase, involved identifying and randomizing eligible clusters (study clinics) and engaging community stakeholders through a Community Collaborative Board (CCB) and Youth Advisory Board (YAB) to assist in the adaptation of the YWHC and S&D reduction training program to the South African geographic and cultural context. This study protocol is based on Aims 2 and 3, the experimental phase of the study. Aim 2 is to evaluate the impact of the HPP S&D reduction training among clinic staff on the use of HIV and SRH services by AGYW, including PrEP, and staff attitudes and behaviors toward AGYW at 4- and 8-month follow-up. Aim 3 is to test the efficacy of a multilevel HIV prevention strategy that addresses structural (S&D reduction), interpersonal , and individual  factors on PrEP readiness, uptake, and adherence; HIV status; and other risk-taking behaviors at 3-, 6-, and 9-month follow-up among vulnerable AGYW. We plan to recruit 900 AGYW across 12 communities in clinic catchment areas for the experimental phase of study.We conducted feasibility assessments of potential study sites in provincial and city clinics in Tshwane, South Africa; 15 clinics were selected as the final study clinics. Each assessment included engaging the clinic manager and requesting permission to conduct the assessment. The selected clinics had (1) community ward-based outreach teams (WBOTs), (2) comprehensive SRH services, and (3) designated youth-friendly nurses and/or services. Other criteria included (a) the jurisdiction of the clinic—city or provincial, as this determines the allocation of resources and infrastructure, (b) reported average number of AGYW visiting the clinic per month, and (c) clinic location  within the Tshwane district. As a result, the final sample consisted of 12 study clinics, 8 provincial clinics and 4 city clinics, with 3 additional clinics as backups if one or more of the selected clinics turns out not to be viable.This cluster randomized trial utilizes a 2 × 2 factorial design  to assesStratified randomization was conducted via SAS Software after clinic selection was finalized. The sample of 12 clinics was first grouped into three strata  based on geographic location type  and clinic administration type/jurisdiction , with four clinics in each stratum. Within each stratum, clinics were then randomly assigned to study conditions based on a 1:1:1:1 allocation. Because there may be important differences pertinent to the outcomes that cannot be made homogenous, such as geographical region, stratified randomization was conducted to achieve even distribution of these factors across study arms. This reduces variability in the estimation of the intervention effect, with resulting increases in power/precision of estimates .The six clinics randomized to receive the S&D reduction training will participate in workshops aimed to reduce clinic staff’s S&D attitudes and behaviors toward AGYW. For the 6 clinics randomized to the YWHC, AGYW participants recruited from communities in clinic catchment areas will be asked to participate in two workshops.At baseline, all clinics (those receiving training and those receiving no training) complete a clinician  or clinic support staff  survey assessing (after providing informed consent) SRH knowledge and service provision, attitudes toward PrEP and AGYW seeking PrEP, and observations of stigmatizing and discriminatory behavior in their clinic toward AGYW seeking services for SRH, HIV, and PrEP  identify as female; (2) HIV negative status; (3) between ages 16 and 24 years; (4) have had condomless sex in the past 3 months with a male partner; (5) not currently pregnant and do not want to get pregnant within the next year; (6) interested in taking a daily pill to prevent HIV (PrEP); (7) not having previously participated in the formative phase of the study; (8) not previously or not currently participating in any other PrEP-related project or research study; (9) not previously or not currently participating in any other HIV study in Tshwane; (10) not on multidrug-resistant tuberculosis (MDR-TB) treatment; (11) lives in one of the target communities; (12) intends to stay in the Tshwane district for the next 12 months; (13) agrees to provide contact information; (14) willing to undergo rapid HIV testing; and (15) willing to undergo pregnancy testing.Because of the eligibility requirement of an HIV-negative and nonpregnant status, interested potential participants must first consent to rapid testing for HIV and pregnancy to confirm eligibility. Additionally, co-enrollment in another HIV study is also checked and any individual who is currently enrolled is excluded.Verbal consent is obtained to screen the potential participant and determine eligibility. Initial eligibility screening of potential participants is performed individually and in private by research study staff. After the initial screening, the next step is to confirm that the participant is HIV-negative, not pregnant, and not enrolled in another HIV study; this is done at the study clinic. Potential participants provide informed consent before conducting these tests. All participants receive a rapid HIV test and a pregnancy test. The only exception is if they have tested negative for HIV the same day and they have an acceptable proof of their HIV testing result, such as a clinic card. If a potential participant cannot be seen for the baseline appointment on the same day as initial screening, they are not tested for HIV and pregnancy until the day of their scheduled baseline appointment to minimize repeat testing. They are rescreened using the initial eligibility screening tool to ensure they meet study eligibility criteria on the day of enrollment.The intake process takes place within the compound of the study clinic, typically in an outdoor tent because of the limited physical space in clinics. Written informed consent or assent is obtained from eligible participants before study enrollment. For potential participants who are younger than 18, consent is required from their mother or a trusted adult woman at least 25 years old who may serve in loco parentis (“in place of a parent”). Parental waiver has been requested to protect a participant’s confidentiality if they are uncomfortable having their mother consent for them. This approach has been used successfully in our previous South African studies with adolescents , 51. In Once the adult woman who will provide consent is identified, study staff schedule an appointment for the potential participant and the adult to sign the mother/in loco parentis consent. The potential participant is screened separately again and assented separately from the adult woman to prevent coercion, maintain confidentiality, and provide the opportunity for the participant to decline. The adult woman is also required to sign a confidentiality agreement form as part of the consent process so they understand that their experience at the project site is confidential and that they must maintain confidentiality regarding the person for whom they consented.After consenting/assenting, participants also sign a release of medical records permitting the release of information on their SRH, PrEP screening and monitoring results, and other referrals and care pertinent to the study.Participants take a breathalyzer test to detect recent alcohol use  and provide urine for drug screening, locator information is collected, and a photograph of the participant is taken to identify the participant for subsequent appointments. This photo is returned or shredded at the final appointment. The participant then completes a baseline questionnaire on a computer tablet via audio computer-assisted self-interview (ACASI) in either English or Setswana  guidelines. Baseline screening for PrEP involves reporting of no MDR-TB (part of the study eligibility criteria), HIV and pregnancy testing (conducted prior to the intake process to confirm HIV-negative and not pregnant), estimation of creatinine clearance, and hepatitis B virus (HBV) screening. Contraindications for PrEP use includes poor renal function (estimated creatinine clearance < 60 mL/min) and absence of the hepatitis B surface antigen and antibody. Presence of HBV is not a contraindication for PrEP; however, liver function monitoring is advised if PrEP is initiated. Participants not eligible for PrEP are linked to the public health clinic to receive the standard of care for each respective medical condition. Individuals who are not eligible for PrEP can still remain enrolled in the study.Participants may decide to initiate PrEP at any time during the study. However, those who do not initiate PrEP during their baseline appointment have to repeat all PrEP eligibility screening. Participants who decide to initiate PrEP are counselled on the importance of adherence and using other protective strategies for up to 20 days of daily dosing before protective levels in vaginal tissue are achieved. Participants are also given guidance on proper management of mild side effects that may occur after initiation and are advised to continue to use condoms and birth control to protect themselves against other STIs and unplanned pregnancy, as PrEP does not provide this type of protection.Clinic visits to test for HIV and pregnancy status are scheduled 1 month after initiation of PrEP and every 3 months thereafter. At 6 months post initiation of PrEP, screening of creatinine levels is conducted to estimate creatine clearance. If a participant tests positive for HIV at any point in the follow-up appointments, PrEP is stopped for that participant and an active referral is provided for test and treat according the South African HIV guidelines. Nonclinical behavioral study data collection follow-up visits continue to occur at 3, 6, and 9 months post enrollment regardless of whether or when PrEP is initiated or when a participant’s PrEP clinic visits take place.All participants who complete their baseline appointment are actively referred to the designated youth-friendly nurse or youth-friendly service at their respective study clinic for SRH services; specifically, birth control services. Follow-up on these linkages is conducted at the 3-month follow-up appointment for participants in the control groups and during monthly check-ins for participants in the YWHC groups.The YWHC workshops comprise a 2-session, 4-module program designed to build on the nexus of substance use, HIV, and GBV by increasing knowledge, skills, and agency to reduce GBV and substance use, and ways to decrease sexual risk and HIV incidence. Previous research in South Africa has shown positive outcomes with the WHC, including that women in the WHC were more likely to use condoms with their boyfriends during their last episode of sexual intercourse, more likely to use female condoms with their boyfriends in the past month, more likely to negotiate condom use, and less likely to report daily substance use at follow-up than women who were not in the WHC , 39, 52.Although the South African National Strategic Plan for HIV, TB and STIs (2017–2022)  outlinesPrEP navigation, which occurs through phone calls and text messaging, provides participants in the YWHC intervention arms who are on PrEP with much-needed support, specifically in the first 1 to 2 weeks of PrEP initiation where many participants may experience minor side effects that often lead to PrEP discontinuation. Study staff work with participants to develop feasible plans that can support the daily use of PrEP, such as the pill boxes they receive, adherence strategies, social support, and addressing other concerns about PrEP. Participants also are reminded about their upcoming refill and check-up appointments. This navigation occurs throughout the study duration as participants are due for their refills.Participants in both study arms return for their 3-, 6- and 9-month behavioral and biological follow-up assessments. Research staff track participants using locator information provided during the intake appointment to help retain participants. The follow-up visit includes reconsenting; updating locator information; a follow-up questionnaire via ACASI; and biological testing for HIV, pregnancy, alcohol use , and other recent drug use. Dried blood spots (DBS) also are collected at these appointments from participants who report to be on PrEP. The PrEP medication used for this study is a combination of FTC 200 mg/TDF 300 mg tablets. The DBS are used to assess the presence of tenofovir diphosphate (TFV-DP), a measure of cumulative and recent adherence, using a previously validated methodology .To protect confidentiality, the study assigns each participant a unique alphanumeric study participant identification number (PID). This PID is the only link between the behavioral and biological data and the identifying information collected for locating participants for their follow-up interviews. Locator forms, consent/assent agreements, and any data that can be linked through the PID are stored separately from other data in double-locked file cabinets in locked rooms at the study’s project site, with restricted access.Data collection for this study is conducted by highly trained staff from the community who develop a rapport with the study participants to engender trust and elicit the most accurate data possible. All staff sign a confidentiality agreement and are trained on the study’s Quality Assurance Protocol and Quality Management Plan (QMP). Study data are encrypted before they are transmitted daily from the field site to secure servers in the United States. The US-based data manager reviews additional automated quality control checks that the software generates each day. If any critical inconsistencies are noted, the data manager contacts the project director and the field supervisor to resolve these inconsistencies. The Principal Investigator, other members of the research team, and the field staff receive daily field activity reports.Procedures have been put in place to address adverse events (AEs) or serious adverse events (SAEs), such as improper disclosure of information or mental or emotional discomfort. As specified in our Data and Safety Monitoring Plan (DSMP), SAEs are reported to the Principal Investigator and the South African Co-Investigator/Medical Director within 24 h of an occurrence and to the Data and Safety Monitoring Board (DSMB), the funding agency, and the Institutional Review Board within 72 h, with appropriate action taken immediately. The study does not interfere with any activities or reports that are part of the public health clinics’ standard operating procedures that do not directly affect the study participants adversely. The DSMP ensures that procedures have been set in place to safeguard the security, validity, and integrity of study data, and that study staff are trained on the policies and procedures for data management according to the Quality Assurance Protocol and QMP. The DSMP also outlines the data analysis plan including preliminary analyses of data for quality assurance and to track the progress of the study.The study established a DSMB comprising three members: a psychologist, an infectious disease clinician, and a bioethicist. The DSMB will meet every 6 months during the trial to review study progress and ensure adherence to the DSMP. This board is independent from the researchers and the study sponsoring institution. Board members discussed whether stopping rules were necessary for this study; they determined that stopping rules were not necessary.The clinic-level primary outcomes for this study include clinic staff attitudes and environment, observed discrimination, and stigmatizing avoidance behaviors toward AGYW, as measured by staff surveys and the clinic audits. The AGYW-level primary outcomes include the level of PrEP readiness, uptake, and adherence (as measured by self-report and DBS), and SRH uptake. The AGYW-level secondary outcomes include frequency of substance use, as measured by the RRBA and biological drug screening and breathalyzer tests to assess recent alcohol use; GBV, assessed through self-reported experiences of emotional, physical and sexual abuse; sexual risk as measured by condomless sex, impaired sex, other sex partners; self-reported frequency of experienced stigma.For the AGYW analyses, the total sample size and number of clusters (clinic catchment areas) were selected to ensure sufficient power to detect meaningful differences in our primary outcomes, while also balancing considerations tied to reducing possible contamination (exposure to the intervention in control clusters) and implementation feasibility with a set number of clinics in the study area. Sample size estimates for tests of two proportions in a cluster-randomized design  were conAnalysis of primary outcome measures will determine whether the provision of S&D reduction training for clinic staff and the YWHC intervention for AGYW will increase PrEP readiness, PrEP uptake, and PrEP adherence, and SRH uptake.AGYW service utilization will be assessed and analyzed through clinic level data at each of the 12 study clinics during an 8-month period pre- and post-training . Baseline and follow-up clinic staff surveys will be analyzed to examine changes in attitudes and stigma at the clinic level. Initial analyses will be descriptive and evaluate group differences comparing intervention and control clinics using unpaired t-tests with unequal variance or nonparametric tests, as appropriate. Using multilevel modeling approach, we will investigate and account for clustering at the clinic level. We will use difference-in-differences (DD) methods as done in another South African study to examine utilization of services by AGYW and staff attitudes and behaviors in the 8 months between intervention and control clinics . The DD m is the average clinic size and r is the interclass correlation estimate. If the Hausman assumption of correlation between the random and fixed effects is violated, then we may include fixed effects representing cluster identification.The testing of Aim 3 will be done by intention to treat analysis, examining the effects of intervention groups at both levels  on PrEP readiness, uptake and adherence. PrEP uptake will be defined as any use of PrEP. We will consider both short-term uptake within the first 3 months after study enrollment and uptake at any point during the 9-month follow-up period. Initially, we will calculate the proportion of AGYW with any use of PrEP, overall, and within each study arm, calculating 95% confidence intervals using the binomial distribution. Given the need to consider the influence of the cluster randomization by clinic, we will use generalized estimating equations (GEE)  models wFinally, we will include additional baseline covariates in the models, including sociodemographic factors and behavioral risks, should initial descriptive analyses suggest differences in the distribution of these factors across study arms. In subsequent exploratory analyses, we will examine the potential mediating and moderating roles of key behavioral, social, and structural factors hypothesized to influence PrEP uptake , as outlined in Analyses of secondary outcomes will use similar analytic approaches and examine hypotheses tied to intervention effects on behavioral risk endpoints  and on AGYW’s assessment of stigma . Other model specifications, such as zero-inflated Poisson or negative binomial will be considered for count outcomes  that have excess zero values or overdispersion.From the AGYW outcomes, it is hypothesized that AGYW enrolled from clinics who received clinic-level S&D reduction training will have higher PrEP and SRH utilization than AGYW enrolled from clinics that did not receive training. AGYW enrolled from clinics that are randomized to receive the YWHC intervention will have higher PrEP readiness, uptake and adherence than those enrolled from clinics that are randomized to PrEP and SRH provision only. AGYW enrolled from communities in clinic catchment areas that are randomized to receive the YWHC will report less HIV-related risk at follow-up  than those enrolled from clinics that are randomized to PrEP and SRH provision only.Missing data in terms of data management may occur because of nonresponse and study attrition. We will analyze differential attrition in relation to participants’ key demographic characteristics. Based on our prior research conducted in South Africa with AGYW who engage in sex risk behaviors, we estimate an average retention rate of 90% over the repeated follow-ups , 37, 62.The experimental phase of the study was approved by the South African Medical Association Research Ethics Committee (SAMAREC), which serves as the Institutional Review Board (IRB) of Record, in addition to the Tshwane District Health Research Committee and the Skills Development for Tshwane Municipal Clinics. Since receiving approval to conduct the full study, we amended the protocol to improve the study design and procedures. Table With COVID-19, there have been barriers and disruptions to PrEP initiation and dispensing, which may alter some of the expected study outcomes, study activities and data collection. We attempted to address these unprecedented circumstances  developing a partnership with the South African Department of Health to reduce S&D by clinic staff; (2) engaging the study’s YAB and the CCB in the adaptation of the YWHC (YAB) and the S&D (CCB) interventions, study marketing materials (YAB), S&D reduction training (YAB) as stakeholders to share their voices, and the regular meetings. This is an important step towards involving community members in the dissemination and implementation of HIV-prevention structural interventions. Support for structural changes may increase when the people whom the intervention is likely to affect participate in the process ; and (3)Few interventions currently exist that address the multiple levels of the psychosocial and community barriers that prevent AGYW from accessing healthcare services. The adapted YWHC provides a more comprehensive HIV prevention toolkit with PrEP and reproductive health as next generation science. If found to be efficacious, the YWHC plus addressing the structural S&D may help reduce barriers to HIV prevention among a key population with the greatest incidence—offering more hope for an HIV-free generation of young women.Recruiting.Additional file 1: Figure File 1. CONSORT Diagram.Additional file 2: Supplementary File 1. Clinician baseline survey.Additional file 3: Supplementary File 2. Support staff baseline survey.Additional file 4: Supplementary File 3. AGYW baseline survey.Additional file 5: Supplementary File 4. Estimated Detectable Differences in PrEP Uptake between AGYW in the PrEP/SRH + YWHC arm vs. PrEP/SRH only, controlling for intervention arm of clinic.Additional file 6: Supplementary File 5. Spirit checklist.Additional file 7: Supplementary File 6. Ethical approval proofs.