To evaluate and summarize the best evidence for nonpharmacological management of chemotherapy induced nausea and vomiting (CINV). This article aims at serving as a reference for nursing staff to prevent and manage CINV.  We systematically searched for evidence on CINV in databases such as Cnki and Wanfang, guide websites such as GIN and NZGG, and professional websites such as UICC and ACS. Only articles published between November 2012 and November 2021 were considered for inclusion in the summary. Two researchers evaluated the quality of the literature and extracted the data.  A total of 22 articles were included in this study, including 3 clinical decisions, 2 guidelines, 1 evidence summary, 2 recommended practices, 13 systematic reviews, and 1 expert consensus. Finally, 15 pieces of evidence were summarized from 3 perspectives: risk factor assessment, nursing process specification, and nonpharmacological interventions.  Our research summarizes the best evidence on nonpharmacological management of CINV. During actual clinical application, it is necessary to fully consider the clinical situation, combine professional judgment with patients' wishes, follow the principle of individualization, analyze the obstacles and facilitating factors of the application of evidence, and prudently apply the evidence to the clinical practice. Chemotherapy induced nausea and vomiting (CINV) is the most common adverse reaction during chemotherapy in cancer patients . FrequenThis study aims at identifying nonpharmacological measures that can effectively prevent and manage CINV. To obtain the best evidence, the PICOS principle is utilized to form the initial questions for evidence-based care. In the context of this study, the P (for “population”) refers to cancer patients age ≥ 18 years. The I represents “intervention” and refers to the various nonpharmacological measures that could prevent, manage, treat, or nurse CINV. The C stands for “comparison”, which is the current clinical nursing measure. The outcome, or O, refers to the outcome index for CINV, which includes physiological and psychological indicators. Lastly, S stands for “study design” and, in this study, refers to clinical decisions, guidelines, evidence summaries, recommended practices, systematic reviews, and expert consensus.∗/diet/early mobilization/exercise∗/rehabilitation/transcutaneous electrical stimulation electrical stimulation/acupuncture/acupressure/herbal/moxibustion/auricular point/massage/relaxation/touch/systematic desensitization/music/aromatherapy/hypnosis/guided imagery/complementary/alternative/non-pharmacological,” and “prevention/treatment/therap∗/management/nurs∗/care/educat∗/train∗/Intervention.”Using the “6S” evidence model, evidence retrieval time was from November 2012 to November 2021. The databases were UpToDate, BMJ, Zynx, DynaMed, Clinical key, Cochrane, Joanna Briggs Institute Library, EBSCO Nursing Reference Center, CINAHL, Web of Science, PubMed, Embase, ProQuest, CBM, Cnki, Wanfang, and VIP. Guidance website included WHO, Medlive, American Society of Clinical Oncology (ASCO), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), New Zealand Guidelines Group (NZGG), National Institute for Health and Care Excellence (NICE), Guidelines International Network (GIN), and National Guideline Clearinghouse (NGC). Professional Society website included American College of Physicians (ACP), Union for International Cancer Control (UICC), American Cancer Society (ACS), and Registered Nurses Association of Ontario (RNAO). The Chinese search keywords were “chemotherapy,” “Nausea/Vomiting/Retching,” and “Cognitive/Behavioral/Diet/Exercise/Functional Exercise/Acupuncture/Moxibustion/Electroacupuncture/Acupressure/Auricular/Soothing/Music/Aromatic/Hypnotic/Imagination/Supplementation/Substitution/Non-pharmacological.” The English search words were “chemotherapy induced nausea vomiting/CINV/chemotherapy nausea/chemotherapy vomiting/chemotherapy emesis,” “cognitive/behavThe inclusion criteria for literature were as follows: (i) the subjects were patients aged ≥ 18 years and underwent chemotherapy. (ii) The study was related to nonpharmacological prevention and treatment of CINV. (iii) The types of literature included clinical decisions, guidelines, evidence summaries, recommended practices, systematic reviews, and expert consensus. (iv) Publication language was Chinese or English.Literature was excluded if (i) the researchers were unable to obtain the full text or an article was incomplete; (ii) it was published repeatedly; (iii) it was a conference report; (iv) it was of low quality.Evaluation criteria were selected for quality evaluation based on literature type. The quality evaluation criteria for guidelines were from the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) . SystemaTwo researchers independently completed the quality evaluation of literature. Conflicts of evaluation opinions between the researchers were resolved through discussion or through evaluation of the literature by a third investigator. When evidence conclusions from different sources were repeated or conflicting, researchers followed the inclusion principle of prioritizing evidence based, high quality, and more recently published evidence.A total of 2985 articles were retrieved for this study, with 2708 remaining after removing duplicates. 59 articles were obtained after primary screening. Finally, 22 articles were obtained after full-text reading and rescreening, including 3 clinical decisions, 2 guidelines, 1 evidence summary, 2 recommended practices, 13 systematic reviews, and 1 expert consensus .AGREE II was used to evaluate the quality of 2 guidelines , 13. TheQ: question.All included evidence was graded using the Australian JBI Evidence-Based Health Care Centre Evidence Recommendation Rating System (2014 Edition) . AccordiThe quality of the included studies directly affects the accuracy and reliability of evidence. In this study, we systematically searched the relevant databases, strictly screened and evaluated the quality of the literature, and extracted and integrated the best evidence from clinical decisions, guidelines, evidence summaries, recommended practices, systematic reviews, and expert consensus involving nonpharmacological management of CINV. The two included guidelines , 13 haveα values are 0.77 and 0.82 for patient self-assessment and primary caregiver assessment, respectively [Chemotherapy drug related factors and patient intrinsic factors can affect CINV . Among tectively . It is rectively .Jie and Chunlan  conducteNonpharmacological interventions are often used as complementary therapies for CINV. Patients love these treatments because they are affordable, convenient, and easy to use. These interventions include auricular point therapy, aromatherapy, ginger therapy, music therapy, relaxation therapy, diet therapy, acupressure therapy, acupuncture therapy, and moxibustion therapy. It is recommended to use acupressure, acupuncture, and other comprehensive methods combined with antiemetics to relieve CINV symptoms in cancer patients, which effect is superior to traditional drug therapy alone .(1) Auricular Point Therapy. Auricular point therapy can be used as an adjuvant therapy in the prevention and treatment of CINV [Vaccinium vulgare seeds or magnetic beads. The Shen men, stomach, sympathetic, or subcortical are often selected as the main points. The liver and spleen are often selected as matching points. A compression effect is then created from the De-qi acuesthesia [ of CINV . This th of CINV  used auresthesia , 18, 32.esthesia  added lu(2) Aromatherapy. Aromatherapy is a therapy using essences, essential oils, and aromatic hydrosols extracted from aromatic plants [c plants . Aromathc plants . It is rc plants . Moreovec plants . The the(3) Ginger Therapy. UpToDate summarized six randomized controlled trials exploring the effect of ginger as an adjuvant therapy for CINV. The results are inconsistent. Three studies found ginger to be beneficial to this end, while the remaining three failed to find any benefits [benefits . Patientbenefits . At thisbenefits , 11, 21.(4) Music Therapy. Music therapy is based on psychology. It entails applying a unique acoustic frequency to regulate physical and psychological symptoms, which is conducive to divert patients' attention, stabilizing mood, and ultimately reducing CINV [ing CINV . Clinicaing CINV , after cing CINV , 42.(5) Relaxation Therapy. Relaxation therapy mostly refers to progressive muscle relaxation—the gradual contraction and relaxation of muscle groups to relax the whole body, thereby reducing the excitability of the sympathetic nervous system and the sensitivity of the emesis center, which has a positive effect on the treatment of CINV [ of CINV , 30. To  of CINV  applied  of CINV .(6) Diet Therapy. Diet therapy for CINV primarily includes implementing reasonable eating habits, eating patterns, and food choices. Nurses should instruct CINV patients to avoid greasy, spicy, sweet, and irritating foods with strong odors. Patients should choose foods that are high calorie, high protein, low fat, and vitamin rich. Ideally, patients should consume digestible liquid or semiliquid diets as much as possible [possible . Patientpossible . Patientpossible , 25, 30.possible  formulat(7) Acupressure Therapy. The goal of acupressure is to dredge the meridians, invigorating the spleen and stomach by stimulating local or systemic acupoints. Neiguan is the most commonly used acupoint in clinical practice [practice . Pressinpractice . It is apractice . In addipractice . Acuprespractice .(8) Acupuncture Therapy. As a characteristic method of external treatment in traditional Chinese medicine, acupuncture therapy regulates the body's neurohumoral system along the meridians, which affect gastrointestinal motility and visceral sensations, thereby treating CINV [ing CINV , 11. Theing CINV . Tai [44ing CINV . Alternaing CINV .(9) Moxibustion Therapy. Moxibustion passes through the venation to reach the meridians and plays a role in regulating Qi, invigorating spleen, and stopping vomiting in the stomach. Modern studies [ studies  have fou studies , 27. Med studies . Qian et studies  found thThis study systematically summarizes the best evidence for nonpharmacological management of CINV from three standpoints: risk factor assessment, nursing process specifications, and nonpharmacological interventions for CINV. Overall, evidence on this topic was of great quality and has scientific validity and clinical utility. In this study, nonpharmacological interventions such as auricular point therapy and aromatherapy are the most ubiquitous techniques for traditional Chinese medicine nursing in clinical practice, which can treat CINV effectively. However, the frequency and duration of some interventions have not yet been established or standardized; clinical operability and generalizability remain insufficient. Future studies should be of higher quality, have larger sample sizes, be conducted in multicenter settings, establish a unified theoretical system, and practice norms to provide more scientific and standardized guidance about nonpharmacological interventions for CINV. Medical staff need to comprehensively evaluate the feasibility of nonpharmacological interventions, fully consider patients' wishes, follow the principle of individualization, and prudently apply evidence to clinical practice. Health staff should specifically analyze the obstacles and facilitating factors in evidence application, formulate targeted action strategies, implement changes at the individual and organizational levels, and implant high-quality evidence in clinical practice.


Physiotherapists deliver evidence-based guideline recommended treatments only half of the time to patients with musculoskeletal conditions. Physiotherapists’ behaviour in clinical practice are influenced by many cognitive, social, and environmental factors including time and financial pressures. Many initiatives aimed at improving physiotherapists’ uptake of evidence-based care have failed to appreciate the context involved in clinical decisions and clinical practice. Therefore, we aimed to describe: i) opinions toward evidence; ii) how evidence is accessed; iii) factors influencing evidence access; iv) factors influencing evidence application, for physiotherapists working in regional areas.We used a mixed-methods study with online survey and focus groups. We included registered physiotherapists in the survey and physiotherapists practising in regional New South Wales in the focus groups. Quantitative and qualitative data were used to inform all research objectives. We used eight domains of the Transtheoretical Domains Framework to design survey questions. We analysed quantitative and qualitative data in parallel, then integrated both sources through by developing a matrix while considering the Transtheoretical Domains Framework domains to generate themes.n = 41; focus group only n = 8; both survey and focus group n = 8). Participants reported that evidence was important, but they also considered patient expectations, colleagues’ treatment choices, and business demands in clinical decision making. Physiotherapists reported they access evidence on average 30 minutes or less per week. Competing demands like business administration tasks are barriers to accessing evidence. Participants reported that patient expectations were a major barrier to applying evidence in practice. Environmental and systemic factors, like funding structures or incentives for evidence-based care, and social factors, like lacking or having a culture of accountability and mentorship, were reported as both barriers and enablers to evidence application.Fifty-seven physiotherapists participated in the study (survey only This study provides context to physiotherapists’ opinion, access, and application of evidence in clinical practice. Physiotherapists’ provision of evidence-based care may be improved by enhancing structural support from workplaces to access and apply evidence and exploring discrepancies between physiotherapists’ perceptions of patient expectations and actual patient expectations.The online version contains supplementary material available at 10.1186/s12913-022-08741-5. Contextual factors that impact evidence-based care provision are appreciated but rarely systematically assessed in implementation research.Although physiotherapists consider evidence important, clinicians must contend with multiple contextual factors when making clinical decisions and accessing and applying evidence in practice, for example business demands and patient expectations.While contextual factors impacting evidence access and application may often be difficult to alter, we discuss potentially modifiable targets for future strategies to improve evidence-based care provision.Physiotherapists deliver guideline recommended treatments only half of the time to patients with musculoskeletal conditions . PreviouPhysiotherapists’ behaviour in evidence-based practice is influenced by a host of contextual factors, such as workplace resources or organisational culture –23. ImprIDescribe the opinions of physiotherapists working in regional areas toward evidence in relation to their clinical decision making.IIDescribe how physiotherapists working in regional areas access evidence.IIIDescribe the factors influencing physiotherapists working in regional areas evidence access.IVDescribe the factors influencing physiotherapists working in regional areas evidence application.Our objectives were as follows:This study was embedded into the establishment of a practice-based research network for physiotherapists in regional Australia, which aims to co-produce research evidence and improve the local uptake of evidence-based care for musculoskeletal conditions. To address research objectives, we used a mixed methods design involving online survey and online focus groups. Quantitative and qualitative data from survey responses were used to inform all research objectives. We wanted to quantitatively describe contextual factors involved in clinical decision making (objective one), patterns of evidence access (objective two), and Theoretical Domains Framework (TDF) constructs (version one) involved in accessing and applying evidence (objectives three and four) . The TDFWe were interested in the context surrounding physiotherapists practising in regional Australia ; location of practice; clinical area .Opinions about evidence in relation to clinical decision making.Amount of time per week participants reported accessing evidence, in various mediums.Barriers to evidence access and application. This was assessed using 12 five-item Likert scale questions, each assessing agreement to the following statement, ‘It’s hard to apply evidence because, … ’. Here, we listed TDF domains . Each of the 12 TDF domains includes a number of constructs, which researchers can include in qualitative or quantitative assessment health professional behaviour . We usedEnablers to evidence access and application. Participants were asked to rate four enablers on a five-item Likert scale.The survey consisted of five sections  database . Online Quantitative and qualitative data were organised separately before we used a mixed-methods analysis to develop themes. We organised and described quantitative survey data as either means and standard deviations or frequency counts and proportions of the total sample. As this was an exploratory study, we did not perform a power calculation for quantitative data.CG transcribed and cleaned audio files from the focus groups and then de-identified and organised data in Nvivo 12 . Two resFirst, we created a ‘baseline’ matrix for each research objective , 45. TheSecond, CG created an ‘expanded’ matrix by adding extra rows unrelated to TDF domains, where there was agreement between qualitative data categories (groups of similar codes) and quantitative data –48. CG tThird, CG, SD, KB, and CW refined the theme matrix by discussing the relationships between themes –50. We rFollowing our mixed-methods analysis, we determined any differences between regional physiotherapists’ survey data and all survey responses by performing a subgroup analysis of regional physiotherapists’ data only.Both CG and SD, who coded data, are physiotherapists with lived experience of the challenges to accessing and applying evidence in practice. CG has professional relationships with many focus group participants. This shaped data collection, analysis, and theory development.n = 41; focus group only n = 8; both survey and focus group n = 8) who ranged in clinical experience, predominantly practised in regional Australia , and had a musculoskeletal clinical focus  (Table n = 1) were included in the analysis. Due to our recruitment methods for the online survey, a response rate cannot be calculated . All participants who were invited to focus groups took part.The total sample consisted of 57 physiotherapists .Nearly all survey participants (96%) considered evidence as either important or very important in clinical decision making. Most survey participants (86%) also agreed that evidence informs their treatment choice. For example, one participant described:Participants reported it is important to consider many other factors when using evidence in clinical decision making. Patient expectations were either important or very important when making clinical decisions for most survey participants (90%). 77% of survey participants rated colleagues’ choices as important or very important and participants reported the clinical environment can shape clinical decisions.“As far as delivering high quality care, I have always struggled with that one. I feel like it’s really hard to give a good treatment in a short period of time that’s financially viable that a person is willing to pay for.” .Participants reported that other considerations of clinical practice, like experience and business demands may sometimes conflict with evidence. For example:Quantitative results for objective two are provided in Table Physiotherapists dedicate a small amount of time to accessing evidence, using multiple different mediums. Over 50% of survey participants reported spending 30 minutes or less per week on accessing evidence, across all mediums.:“If any physio related stuff comes up, I’ll usually notice it and triage if I’m actually going to read it or not.” .Participants reported engaging in quality assessment (triaging) when accessing evidence, but it is unclear what such quality assessment entails. For exampleWe report the results of research objective three by TDF domains. Table The evidence is out there, and people have access to it.” .“Most survey participants (84%) disagreed that it is ‘hard to find evidence’, while 55% disagreed that it is ‘hard to access evidence’. Participants expressed that they know how to access evidence, meaning the TDF domains of knowledge about skills, were not barriers. One participant reported:Paywalls were reported as a barrier. However, participants also reported that removing paywalls would make it easier to access evidence.Participants reported time as a barrier to accessing evidence, and this time limitation is driven by competing demands, for example, seeing patients or fulfilling business administration tasks. For example, one participant expressed difficulty in prioritising accessing evidence over other competing demands:Not only are we trying to stay abreast of current evidence and trying to incorporate that into our practice. Most business owners, like myself, carry a bigger caseload than they should. And then with what time you have left over after doing all that, you’re trying to run a business.” .“Participants also reported that using social media facilitates evidence access, as they frequently use social media for other reasons like connecting with friends.We report the results of research objective four by TDF domains. Table Skills were a barrier to research application; participants reported that the skill of critical appraisal is difficult in the context of the ever-increasing amount of evidence.Patient expectations were a barrier to research application in two ways. 60% of survey participants agreed to the statement, “it’s hard to incorporate evidence into practice because patients expect certain treatments that aren’t evidenced based”. Participants reported that perceived impacts on the therapeutic alliance is a barrier to applying evidence. They viewed that the consequences of choosing one treatment over another may have negative effects on the therapeutic alliance between clinician and patient. For example:“Again, if you’re not building that rapport and trust initially, everything else you do isn’t gunna [going to] be taken on board.” .System factors were reported as both barriers and enablers to evidence application. Participants reported healthcare funders often do not require care to be evidence-based, therefore physiotherapists experience a lack of financial incentive to apply evidence in practice. For example:“But right now, it doesn’t work like that. So, we have the clinicians who choose to deliver largely what they want and if it’s loosely physiotherapy, most of it is paid for.” .“And I don’t know how you can stamp out that practice without some sort of accountability structure on a more systemic level.” .Consequently, participants suggested funding structures supportive of evidence-based care would encourage physiotherapists to apply evidence in their clinical practice. For example:“I wonder if it’s about how you can incentivise but create the structure around making the right thing to do easy.” And “That is systemic that doesn’t require practitioners to have to consciously make a decision all the time to behave this way. That it’s built in to their, more than culture, the system somehow.” .Participants also reported system factors could function as an enabler to evidence application by facilitating clinical decision making to preference evidence-based options, rather than non-evidence-based options. For example:Participants noted several factors in their social environment that either facilitated or hampered applying evidence in clinical practice. Participants reported that a lack of professional culture towards accountability to evidence-based care standards may be a problem, and consequently, developing such cultures may enable better application of evidence in practice.Participants also reported that mentorship can be both a barrier and an enabler to evidence application. For example, one participant expressed the downside of poor mentorship:“If bosses are pretty set in their ways, maybe not staying up to date, and are educating new grads on traditional ways of physio, then it’s not likely that things are going to move forwards.” .However, 86% of survey participants agreed with the statement, “It would make it easier to apply research evidence if I were able to connect with other like-minded clinicians to discuss applying evidence in practice.”Participants questioned research relevance to their practice. 65% of survey participants agreed with the statement, ‘it’s hard to apply research evidence because research doesn’t answer my clinical problems’. For example, one participant reported:“Researchers are really good at asking questions, but sometimes the questions aren’t that relevant for us.” .“There’s some really good, high-quality research out there but you can’t implement it, because it’s so controlled and it’s so sterile and it’s got nothing to do with what we do in our clinic or practice.” .Participants also reported that evidence may not be implementable in clinical practice. For example:“I sort of need researchers to better understand what clinic life is like. So that they’re asking better questions.” .Most participants noted that improving evidence relevance would be helpful. 78% of survey participants agreed that it would be easier to apply evidence if they were supported to answer questions relevant to their patients or clinic. For example:In our study, participants reported that evidence is important when making clinical decisions, but it is only one factor among many to consider in clinical practice. Participants report dedicating small amounts of time weekly to accessing evidence across different kinds of mediums. Participants indicated addressing contextual barriers would ease evidence application and suggested removing paywalls, better mentorship, funding of evidence-based care, and establishing a culture of accountability within the profession may result in improvements.We have defined and explored two specific behaviours in our study; evidence access and application. Most studies fail to isolate specific behaviours involved in evidence implementation, instead referring to a confusing array of terms and behaviours –11. We hThe focus groups had a dual focus; to inform the research objectives and inform the establishment of a practice-based research network for physiotherapists. The network had the explicit purpose of co-designing and implementing more clinically relevant evidence. This likely altered participants’ perspectives towards evidence relevance as both a barrier and enabler to evidence application. Participants held a highly positive opinion of evidence, which may not be representative of the profession more generally. However, this limitation is likely a feature of most qualitative research investigating physiotherapists’ opinion of evidence –53. Our Although our study demonstrates many factors can be both barriers and enablers to research access and application, we will limit our discussion to potentially modifiable contextual factors.Social factors are a well-recognised modifiable factor to improve the uptake of evidence into practice –25. Our More effort is needed to understand how physiotherapists prioritise evidence access among the competing demands of clinical practice. Participants consistently report time pressures as a barrier to evidence uptake and implementation , 8–11. HParticipants in our study reported that patients may expect certain treatments that are not evidence based, which makes applying evidence difficult. Participants indicated they provide non-evidence-based care options to preserve the therapeutic alliance. The original description of evidence-based practice clearly outlines that clinicians should incorporate and respect patient preferences . AlthougOur results demonstrate that a lack of clinically relevant evidence is a significant barrier to applying evidence in practice. Irrelevant research can stem from researchers focusing on problems that are not significant problems for clinicians or including treatments that can’t be readily implemented in practice –15. ThisThis study places physiotherapists’ opinion, access, and application of evidence into the context of clinical practice. Although physiotherapists consider evidence important, it is one among many factors that must be considered when making clinical decisions. Competing demands of clinical practice, like business administration, must be prioritised alongside accessing evidence. Some contextual factors like system and structural factors, for example funding structures, may be difficult to alter. However, physiotherapists’ provision of evidence-based care may be improved by enhancing structural support from workplaces to access and apply evidence and exploring discrepancies between physiotherapists’ perceptions of patient expectations and actual patient expectations. Researchers and clinicians working collaboratively may ensure research answers more relevant questions and is more considerate of the context of clinical practice.Additional file 1: Appendix 1.Additional file 2. Online supplement 1.Additional file 3. Online supplement 2.


We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency,  SICI is abnormally reduced in several neurological disorders4, has recently informed the differentiation of dementia subtypes5, and has been found to predict response to TMS neuromodulation6. However, SICI assessment is influenced by inter-individual differences in the neural populations activated by TMS8, and this relationship may explain up to half of the inter-individual variability observed in SICI7. Indeed, it has been suggested that levels of SICI may depend on individual patterns of TMS neural recruitment as much as they do on the inhibitory activity that SICI attempts to assess9. Although SICI provides a valuable non-invasive marker of GABAergic activity, our understanding of how SICI assessment is affected by individual differences in the neural populations recruited by TMS remains incomplete.Short-interval intracortical inhibition (SICI) is a paired-pulse transcranial magnetic stimulation (TMS) technique that provides a non-invasive indication of intracortical inhibitory activity mediated by gamma-aminobutyric acid (GABA) A receptors10. Invasive epidural recordings reveal that TMS delivered over the primary motor cortex (M1) elicits a descending cortico-spinal volley (CSV) of distinct waves, and individual waves are currently thought to represent activity in non-identical neural populations12. The CSV can produce a motor evoked potential (MEP) in peripheral muscle, which is quantifiable with electromyography (EMG)14. The onset latency of these MEPs can be used to indicate the likely neural populations activated in an individual11. Higher intensity latero-medially (LM) directed stimulation can directly activate axons of cortico-spinal neurons. Here the CSV commences with its earliest possible component, known as a direct (D) wave, and the later components, termed indirect (I) waves , are generated by trans-synaptic activation of cortico-spinal neurons15. The presence of D waves in a CSV evokes MEPs of the shortest latency, which can be used to control for individual differences in the cortex to muscle pathway16. Lower intensity TMS delivered using posterior-anterior (PA) directed current tends to evoke a CSV commencing with an earlier I1-wave. Here, the latency of the CSV and resulting MEP is 1–1.5 ms longer than when D waves are present. Using an anterior–posterior (AP) directed current tends to evoke CSVs commencing with a later I wave (often corresponding to the I3 wave), and the resultant MEPs are approximately 3–7 ms later than D wave latency17.  can reveal inter-individual variations in the neural populations activated by TMS19.  that appear to be inhibited by SICI, any early I waves present during the test are not reduced in amplitude8. One reported an association between AP latency and SICI assessed in the PA direction8 and another reported a strong association between AP latency and AP SICI7. In both cases, longer MEP latency differences were associated with greater assessed inhibition, in line with what would be expected given the specific interaction each measure has with the CSV. Both of these studies utilized threshold tracked (tt) SICI where the TS intensity is increased until it overcomes the inhibitory influence of the CS22. Given that adjustment to stimulus intensity is known to alter CSV composition23, and that the composition of the CSV appears to drive the relationship under investigation, we therefore investigated the untested relationship between conventional amplitude-ratio SICI (where the TS intensity is held constant) measured in the PA and AP current directions and MEP latency difference. We expected that greater SICI would be associated with longer latency difference.Two recent reports have begun to describe the practical nature of the relationship between SICI and MEP latency differenceM = 25.22; SD = 5.37) were recruited from an Australian university and surrounding area via online and poster advertisements. Standard TMS exclusion criteria and pre/post safety screening procedures were applied25, including exclusion of potential participants with any self-reported history of neurological or psychological disorder, or current medical or recreational use of psychoactive drugs. The study was approved by the Deakin University Human Research Ethics Committee and all participants provided written informed consent in accordance with the Declaration of Helsinki.Twenty-eight  healthy right-handed participants aged 18–42  muscle of the right hand. Wet gel 10 mm Ag/AgCl electrodes were applied in a belly-tendon montage, grounded on the ulnar styloid process. EMG signals were amplified , bandpass filtered (1 Hz–2 kHz), digitized , and recorded (LabChart 8.0—ADInstruments) from 200 ms before to 300 ms after TMS pulses2 system (Magstim United Kingdom) and delivered with a 70 mm Magstim figure-8 coil via the Bistim connecting module. Hotspot and thresholds were assessed via single pulses delivered in Bistim mode, latency and SICI blocks were assessed in independent Bistim triggering mode27. The left M1 FDI hot spot for the contralateral right hand was located in accordance with previous guidelines26 using PA current . The hot spot location was marked in a neuro-navigation system  and used for all subsequent TMS. Coil position was continually monitored throughout the experiment using the neuro-navigation system. Coil position errors were low with an average (and SD) distance from the hot spot of 1.15 (0.80) mm, tilt away from the target of 2.06 (1.59) degrees and a mean absolute twist error of 1.59 (1.50) degrees. Motor thresholds were assessed with 30 TMS pulses using maximum-likelihood parameter estimation by sequential testing, implemented in the TMS Motor Assessment Tool 2.028, to establish a stimulus intensity with a 50% probability of eliciting an MEP meeting the target criteria. For active motor threshold (AMT) which was assessed in PA, AP and LM current directions, the MEPs meeting criteria had amplitudes greater than 100 µV29, were distinguishable from background EMG, and occurred within a physiologically possible latency range (15–35 ms). During active thresholding, and subsequent latency assessments in active muscle, participants maintained a slight voluntary contraction of the FDI muscle . Stimulus intensity with a target amplitude of 1 mV (SI1mV) was assessed in resting muscle in PA and AP current directions.Monophasic TMS pulses of 100 µs rise time and 1 ms duration were generated with a Magstim Bistim16 using PA, AP, and LM current directions, with intensities determined by reference to the thresholds established in each direction. For PA and AP latencies in active muscle, 20 trials were assessed in each direction using a stimulus intensity set at 110% AMT. LM latencies were assessed with 10 trials in active muscle, and a stimulus intensity of 150% AMT in order to increase the likelihood of evoking an MEP commencing with a D wave30. Here, as previously16, 10 trials at this higher stimulus intensity provided sufficiently reliable latency estimates31. MEP onset was also assessed in the unconditioned test pulses used to calculate SICI. These comprised 20 trials delivered at SI1mV in resting muscle, using both PA and AP current.MEP onset was assessed as per Hamada et.al33. The intensities were determined with reference to the relevant thresholds established in each direction. Twenty SICI conditioned trials and 20 single pulse SI1mV trials were interleaved and jittered with 5, 6, and 7 s inter-stimulus intervals in pseudo-randomized order.SICI was assessed in resting muscle in the PA and AP current directions. The CS was delivered at 90% AMT, followed 2.5 ms later by the TS delivered at SI1mV34, and also alter SICI35, any trials with EMG amplitude greater than 20 µV in the 100 ms prior to the stimulus  were excluded from SICI calculations. Because SICI calculation relies on averaged amplitudes, we made a pragmatic decision that any average amplitudes calculated from less than 5 MEPs were likely unreliable36 and therefore were not calculated. This meant that in any block of 20 SICI trials (conditioned or unconditioned) the median number of trials averaged was 18 . We ultimately calculated SICIPA magnitudes for 23 participants and SICIAP magnitudes for 25 participants. MEP latencies were calculated for each participant and each group of latency trials using a custom Matlab script. EMG signals for the block were averaged8 and the latency was identified as the first timepoint following 15 ms post stimulus where the averaged signal exceeded the mean plus 5 standard deviations of the averaged signal in the 100 ms prior to the stimulus. Any pulses that did not reach their individual 5 standard deviation threshold  were excluded from the averaging. Because latency can be altered by voluntary contraction23 any resting latency trials with EMG amplitude greater than 20 µV in the 100 ms prior to the stimulus  were also excluded from the averaging of EMG signals for resting PA and AP latency detection. Because MEP latency is more reliable than MEP amplitude37 we made a pragmatic decision that latency should only be calculated where at least 3 trials were available to create the averaged EMG signal. This meant that in any block of 20 latency trials the median number of trials averaged was 16 , and for LM latency all blocks were averaged from 10 trials. We ultimately obtained PA and LM active latencies for all (28) participants, AP active and AP resting for 27 participants, and PA resting for 26 participants. The averaged traces and detected latencies were plotted for visual inspection revealing 7 clear failures (of the 136 plots), due to noise or dc drift in the signal. These latencies were corrected by manually adjusting the onset to the first subsequent point clearly associated with the MEP response where the EMG signal exceeded the mean plus 5 SD of the pre-pulse EMG16. The mean plus 5 SD threshold was chosen to keep the failed detections, and hence the manual adjustments, to a minimum in order to maximize the objectivity of the extracted latency metric. We also made a further check on our automatically detected latencies  and condition (resting or active) tended to commence with earlier  or later  I waves. The resulting latency difference metrics were PA-LMACT, AP-LMACT, PA-LMREST, and AP-LMREST.For each participant, active LM latency (the indicator of D wave latency) was subtracted from both resting and active PA and AP latencies to create latency difference metricsPA and SICIAP.For each participant and current direction,  SICI was calculated by expressing the average of the conditioned MEP amplitudes as a percentage of the average unconditioned amplitudes (i.e. (conditioned amplitude/unconditioned amplitude) × 100, 100 = no inhibition, below 100 = inhibition). The resulting metrics were SICI23. These comparisons were of the motor thresholds , raw latencies , and latency difference scores . Quantile—standardized residual plots suggested that motor thresholds, raw latencies, and latency difference scores were approximately normally distributed. However none in this series met the assumption of sphericity assessed via Mauchley’s test therefore repeated-measures ANOVA with Greenhouse–Geisser correction applied was used for comparisons. Post-hoc pair-wise comparisons with Tukey’s adjustment were then conducted  was present in SICIAP. This may suggest a degree of caution in the interpretation of the SICIAP Pearson’s coefficients. Family-wise error was controlled separately for the SICIPA and SICIAP comparisons with Holm-Bonferroni adjusted p values. Statistical analyses were performed using RStudio Version 1.4.1106.Scatterplots were assessed prior to the main correlational analyses and indicated no outliers or non-linear relationships were present. Linear correlations (Pearson’s) were used to test for a relationship between SICIDescriptive statistics for SICI magnitudes, MEP latencies, and motor thresholds are reported in Table PA, AMTAP, AMTLM, SI1mVPA, and SI1mVAP), F = 148.82, p < 0.001, ω2 = 0.84. Post-hoc comparisons with Tukey’s adjustment indicated there were significant differences between all thresholds  = 3.02, p = 0.006, Hedge’s gav = 0.68. See Fig. Participants demonstrated significantly greater SICI  when assessed with AP relative to PA current, t3 = 3.02,ACTIVE, APACTIVE, LMACTIVE, PARESTING, APRESTING), F = 69.61, p < 0.001, ω2 = 0.74. Tukey’s post-hoc comparisons  F = 27.69, p < 0.001, ω2 = 0.52. Tukey’s post-hoc comparisons , but no significant differences existed between PA-LMACT and PA-LMREST or AP-LMACT and AP-LMREST. See Fig. There were significant differences in latency difference metrics , and resting FDI, r = − 0.57, r2 = 0.33, N = 24, padj = 0.014, praw = 0.004, (two-tailed). The associations between SICIPA and PA latency differences were weak and not statistically significant , resting, r = − 0.19, r2 = 0.05, N = 24, padj = 0.379, praw = 0.379, (two-tailed). Scatterplots are presented in Fig. Greater SICIAP was not significantly associated with any latency difference: PA-LMACT, r = − 0.20, r2 = 0.04, N = 26, padj = 1, praw = 0.331; PA-LMREST, r = − 0.051, r2 = 0.002, N = 25, padj = 1, praw = 0.807; AP-LMACT, r = − 0.09, r2 = 0.008, N = 25, padj = 1, praw = 0.663; and AP-LMREST, r = − 0.005, r2 = 0.00003, N = 26, padj = 1, praw = 0.980. See scatterplots in Fig. SICIACT and AP-LMACT latency differences  for the interpretation of each measure. Contrary to our expectations, SICIAP was not associated with MEP latency difference.The current study sought to further characterize the nature of the relationship between SICI and inter-individual variations in the neural populations activated by TMS (as assessed using MEP latency difference metrics). The relationship was examined, using both PA and AP current directions, by assessing MEP latency in active and resting muscle, and assessing SICI magnitude in resting muscle. Here we used conventional SICI where, because the test stimulus intensity is held constant, the composition of the test CSV is likely less variable than in the ttSICI examined previously. Our preliminary analyses indicated that mean PA-LMPA, supporting the idea that individual levels of SICI depend on individual tendency toward earlier or later I wave recruitment. Both resting and active AP-LM latencies were closely associated with SICIPA. To our knowledge, this is the first report of an association between AP-LMREST latency and SICIPA, suggesting that, for our current purpose, probing MEP latency at SI1mV in resting muscle may be equally as useful as the more common 110% AMT probe used in active muscle. Our findings also support the previous account of a correlation between AP-LMACT latency and ttSICIPA8, and demonstrate here that the correlation is also apparent when the TS is held constant. While AP-LM latencies do not directly reflect the PA TS used in SICIPA, they are used to infer the extent of an individual’s later I wave recruitment. It seems logical that SICI’s selective inhibition of I3 and later waves, combined with SICI’s lack of impact on early I waves, could be driving the relationships we observed. We did not detect statistically significant relationships between SICIPA and PA-LM latencies. Perhaps PA-LM latency is not sufficiently sensitive to the late I waves inhibited by SICI, however we note the scatterplots and coefficients appear to be in agreement with the direction of the relationship we found for AP-LM latencies.We found that 33% of the observed individual variability in intracortical inhibition assessed with PA current was explained by AP-LM latency difference. As expected, longer AP-LM latencies were associated with greater SICIPA, we observed no linear relationships between SICIAP and any latency difference measure. This was in contrast to a previous report of an association between active AP-LM latency and ttSICIAP7. We acknowledge that our study may be limited by the possibility of a floor effect being present in our conventional SICIAP, as evidenced in the scatterplots and Fig. AP and latency difference. Alternatively, the absence of an association between SICIAP and latency difference measures could be because assessing SICI with AP current avoids early I wave recruitment that would otherwise mask assessed inhibition.Unlike with SICIPA and AP-LM latencies represent the third report of a significant, likely neurophysiologically-driven, and arguably underappreciated relationship between SICI and MEP latency difference. Here we demonstrate for the first time that this association is present for conventional SICI, where test stimulus CSV composition is held relatively constant. Accounting for this relationship could contribute to a more individualized understanding of both GABAergic inhibitory activity and TMS preferential recruitment of distinct neural populations. The major implication here is that interpreting SICI in the context of latency difference could increase the accuracy and utility of the measure. For example, in individuals with short latency difference, who therefore have early I waves present in the CSV, the absence of SICI, i.e. no inhibition of the SICI test pulse, could mean that no later I waves were present to be inhibited, or alternatively that GABAergic activity was not apparent. In these individuals, a test pulse that reveals inhibition indicates the presence of later I waves, but the assessed SICI may only provide a diluted measure of GABAergic activity due to the presence of unaffected early I waves. However, in individuals with longer latency difference who therefore do not have early I waves present in their CSV, the extent of inhibition of the test pulse may reflect a more accurate index of GABAergic activity.Our findings of an association between conventional SICI39. It is possible that the use of long latency difference subgroups may allow for more accurate comparisons of SICI function in clinical and healthy subjects. We also note that differences in I wave recruitment could be contributing to the SICI dysfunction identified in clinical populations. The inclusion of latency difference assessment in future SICI research could speak to this contribution, potentially increasing our understanding of the mechanisms underlying the reduced SICI observed in some clinical groups. A further implication of our findings is that conventional SICIPA may provide a diluted index of GABAergic inhibitory activity. As suggested previously40, SICIAP may deliver a more accurate assessment of intracortical inhibition by avoiding the unaffected early I wave recruitment that might mask assessed inhibition.Greater precision in SICI assessment may be important in clinical investigations that report reduced SICI in a range of neurological disorders44, but because latency can only reflect the first component of the CSV, short latencies cannot speak to the presence of later I waves. In individuals with short latency difference the presence of SICI could indicate that later I waves are also present in their CSVs. We suggest that including SICI assessment in future research could, at the individual level, facilitate a more detailed understanding of how preferential TMS recruitment of distinct neural populations impacts TMS neuromodulation outcomes.There are also implications for interpreting MEP latency. A growing body of research suggests that later I wave recruitment (assessed via MEP latency difference) is associated with TMS-induced neuromodulation outcomes, and with learningOur study used single and paired pulse TMS to examine the relationship between MEP latency difference and SICI assessed using PA and AP current. Latency difference was used to indicate whether individual motor response to TMS tended to commence with earlier or later I waves. We found that a significant proportion of the observed variability in PA SICI magnitude can be accounted for by MEP latency difference, reflecting individual differences in the neural populations preferentially activated by TMS. However, MEP latency difference did not account for the variability we observed in AP SICI. We suggest that interpreting SICI measures in the context of individual I wave recruitment patterns will contribute to more precise assessment of GABAergic intracortical inhibition, that AP SICI could more accurately reflect inhibitory processes, and that accounting for SICI could enhance our understanding of the relationship between MEP latency difference and TMS neuromodulation outcomes.Supplementary Information.


The use of evidence-based (EB) and evidence-informed (EI) criteria in determining the effectiveness of health interventions has been widely adopted by national and international agencies in their attempt to address health gaps, particularly around Ending the HIV Epidemic (EHE) initiatives. Utilization of these rigorous standards has proven critical in making progress towards achieving EHE goals, yet many communities remain unreached and underserved despite widespread adoption of EB/EI standards in public health research and practice. Although a crucial tool for innovative healthcare delivery, emphasis on the use of EB/EI parameters has created bias within the cycle of knowledge creation that favors well-resourced institutions given their capacity to meet the rigorous evaluation standards required of EB/EI science. This bias can systematically exclude institutions more aligned with community needs, such as community-based organizations and other grass-roots initiatives, which may have long-standing interventions that more effectively engage marginalized groups but do not have the capacity to meet EB/EI standards.This paper will explore the manifestation of systematic bias and research inequity in the process of identifying and assessing EB/EI HIV care interventions through the lens of a Health Resources and Services Administration funded initiative, coined the Center for Innovation and Engagement, which supports people living with HIV in the United States. An overview of the initiative is provided along with examples of how promising interventions with positive outcomes for members of marginalized communities are excluded in place of interventions that meet traditional standards of scientific rigor but are not novel or particularly innovative. Themes around academic imperialism and power hierarchies will be considered along with key barriers, lessons learned, and recommendations for promoting more equitable EB/EI research practice.It is crucial for entities supporting public health interventions to prioritize equity and inclusion in all stages of funding, design, and implementation. This is particularly true for conditions, such as HIV, that disproportionally impact the most marginalized. This will require approaching EB/EI research with a critical lens towards power and a willingness to dismantle historical dynamics that perpetuate inequities as a way of encouraging truly innovative solutions to support those who need it most. The use of evidence-based (EB) and evidence-informed (EI) criteria in gauging the effectiveness of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) prevention and care interventions has provided crucial insight into the application of findings for real-world settings, particularly in the realm of implementation science, which examines ways to deliver innovative health tools to people living with HIV (PLWH) and populations disproportionately impacted by the HIV epidemic , 2. ThisThe use of EB/EI criteria in HIV prevention and care represents the long-standing use of critically rigorous standards within scientific research as a way of not only measuring the impact of a given approach but, more broadly, ensuring minimal bias is introduced throughout the process of evidence determination , 12. HowThis article will explore how systematic biases and research inequities manifest in the process of identifying and assessing EB/EI HIV care interventions through the lens of a Health Resources and Services Administration (HRSA)-funded Special Projects of National Significance (SPNS) initiative: Evidence-Informed Approaches to Improving Health Outcomes for People Living with HIV. Themes showcasing elements of academic imperialism will be highlighted along with key barriers to uplifting promising practices, lessons learned from the process, and recommendations to promote equitable EB and EI research practice. The SPNS initiative, coined the Center for Innovation and Engagement (CIE), is led by NASTAD in collaboration with Northwestern University’s Center for Prevention Implementation Methodology and Howard Brown Health Center. NASTAD is a leading non-partisan non-profit association that represents public health officials who administer HIV and hepatitis programs in the U.S. NASTAD’s mission is to advance the health and dignity of people living with and impacted by HIV/AIDS, viral hepatitis, and intersecting epidemics by strengthening governmental public health and community partnerships. CIE goals include identifying, cataloging, and disseminating EB/EI approaches to improve health outcomes for PLWH in the U.S.EB and EI parameters have been revered as a cornerstone of medical practice after its conception in the 1980s as clinical medicine became increasingly more reliant on data and existing academic knowledge . These pEngagement and retention in HIV care is now well recognized as embedded within a broader socio-ecological framework that cannot be addressed with biomedical interventions alone . This ha“Academic imperialism” can only be defined by first understanding the term “imperialism,” and it’s varied manifestations. Imperialism can be defined as “the practice, theory, and the attitudes of a dominant metropolitan center ruling in a distant territory” and has often been used when discussing political, social, and economic power dynamics between nations . ManifesAlthough interventions created through traditional academic avenues continuously prove to be critical tools in HIV public health practice, the imperialism propagated through the unchecked power dynamics inherent to the prioritization of EB/EI approaches has routinized the recycling of well-established interventions for engagement and retention in care under the guise of innovation. This was made evident through NASTAD’s CIE project, in which results from a systematic literature review of interventions were prioritized over data collected at several HIV-related conferences, and a broadly cast request for information (RFI) sent to health departments, CBOs, and AIDS Service Organizations (ASOs) across the U.S. The intervention identification process is summarized in the sections that follow.linkage, re-engagement, and retention in care outcomes. For this review, linkage was defined as the initiation of HIV-related care  for people newly diagnosed with HIV or those that were previously diagnosed and never began treatment; re-engagement as a continuation of treatment or services for those diagnosed with HIV that have fallen out of care; and retention as regular engagement in care after being linked to or re-engaged in care. Included manuscripts should describe studies focused on the effectiveness of a clearly defined intervention or approach and describe linkage, retention, and/or re-engagement outcomes, not including HIV testing interventions with a passive referral or an inadequately described linkage component.A systematic literature review was conducted by Northwestern University to identify evidence-based and evidence-informed approaches and interventions that are designed to engage PLWH who are not receiving or who are at risk of not continuing to receive HIV healthcare. The literature review consisted of several phases of targeted review and exclusion to produce a set of manuscripts describing interventions with A research librarian developed a comprehensive search strategy in collaboration with the review authors. Searches were conducted on December 7, 2018, in the following databases: PubMed MEDLINE, Embase (Elsevier), Cochrane Library and Cochrane Register of Controlled Trials (CENTRAL) (Wiley), PsycINFO (Ebsco), and Web of Science. The PubMed MEDLINE search was adapted for all additional databases using database-specific logic and wildcards. All databases were searched back to 2005, and an English language filter was applied. The search strategy included terms related to 1) people living with HIV/AIDS; 2) treatment uptake, adherence, and retention; and 3) intervention, implementation, and evaluation. As this review was interested in interventions in the United States, citations that discussed countries other than the United States without mention of the United States were excluded using the Boolean NOT feature. This search yielded a total of 21,302 results across all databases after de-duplication. Eligible studies for analysis were identified using a combination of automatic and manual screening processes, as described in Fig. NASTAD developed an RFI survey to identify interventions that have not been published in academic literature using the same definitions described in the literature review process. The RFI was broadcasted through NASTAD’s membership network in conjunction with tailored outreach to a list of over 150 CBOs and ASOs across the country who work closely with marginalized groups, including lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA+) populations as well as racial and ethnic minorities. Data on interventions were also collected using the same RFI structure via conference presentations  from the 2018 National Ryan White Conference on HIV/AIDS, the 2019 National HIV Prevention Conference, 2019 Conference on Retroviruses and Opportunistic Infections, and 2019 SYNChronicity Conference. NASTAD identified 122 interventions, of which 83 met the inclusion criteria for key informant interviews to collect more information on outcomes, as described in Fig. Interventions selected from the literature review and the RFI processes were scored using an evidence rubric developed by Northwestern University in collaboration with HRSA and the Centers for Disease Control and Prevention (CDC). The evidence-based criteria established by the Agency for Healthcare Research and Quality and the CDC was used as a foundation for defining EB, and EI approaches. The rubric used a set of criteria to measure the strength and impact of evidence for each intervention to identify approaches, strategies, or models that are proven effective or show promise for improving the care and treatment for PLWH. The criteria used to measure each intervention’s level of evidence included quality of study design , the quality of intervention implementation and analysis , the strength of the evidence , and additional limitations and strengths not captured by other rubric components. Items within these categories were scored to determine whether the criteria were met and, where relevant, if the criteria were met with greater qualifications .In addition to the evidence rubric, an evidence and dissemination expert panel was coordinated to review the final list of interventions that met the evidence threshold. Members were asked to review the evidence score for each intervention along with a summary of its methodology and outcomes. Through a series of discussions, each expert panel member assigned the intervention an “Impact Score” using a series of categories aimed at gauging the real-world impact of the intervention . Final prioritization of interventions for inclusion in the CIE compendium was determined by the weight of the evidence score and the impact score, along with supplementary feedback from expert panel members. Only one intervention identified through the RFI was included in the final list of interventions for the CIE compendium, while the remaining interventions were identified through the literature review led by Northwestern University.The final CIE compendium consisted of 15 interventions: 1 focused on linkage to care, 2 focused on re-engagement, 9 focused on retention, and 3 focused on a combination of linkage, re-engagement, and/or retention. The majority of interventions constituted innovative service delivery models. NASTAD worked with intervention developers to create detailed implementation guides for 10 of the 15 interventions to serve as replication tools for diverse healthcare settings. Fact sheets were developed for the remaining 5 interventions highlighting key considerations from respective academic manuscripts. Implementation guides, intervention summaries, and supplementary replication resources  were housed on the CIEhealth.org microsite hosted by NASTAD.The process of identifying EB/EI interventions for the CIE compendium highlighted several important considerations for identifying innovative EHE solutions: 1) intervention developers and implementors responding to the RFI had strong anecdotal and clinical evidence suggesting successful uptake of their approaches by patients, yet did not meet the rigorous evaluation standards required for inclusion in the CIE compendium, 2) all interventions selected for the CIE compendium were published in academic journals with the exception of one identified through the RFI, which was in the process of submitting for publication, 3) all interventions were led or substantially supported by universities or academic medical centers, 4) 8 of the 15 final interventions in the compendium already had some form of existing implementation content , and 5) the majority of expert panel members were White, cisgender, and highly trained in academic research and/or medical practice. Most importantly, this process uncovered biases embedded in the EB/EI identification process that reinforce academic imperialism and propagate systemic racism in the way evidence and expertise are prioritized.Examining the implications of using EB/EI evidence-hierarchies in the development of the CIE compendium requires a critical eye for the way evidence is prioritized. A number of interventions identified through the RFI had clinical outcomes that were deemed “promising” by the clinical providers implementing them based on both quantifiable improvements in individual health outcomes and anecdotal feedback from patients. However, none of these implementors were able to rigorously evaluate their work to the statistical degree necessitated by EB/EI criteria for a variety of reasons, including constraints around funding and human resources. For example, ‘Girlfriends Connect,’ an intervention identified through NASTAD’s RFI process, did not make it into the CIE compendium despite reporting 100% linkage when evaluated. The intervention focused on incarcerated transgender women and was the first culturally relevant and theory-based adaptation of the evidence-based intervention, Project START, which is a well-known initiative that met the criteria for inclusion within the CIE compendium despite having already been widely disseminated. The lack of inclusion of an intervention like Girlfriends Connect, even when it was built on the same evidence-based foundation as Project START and provided promising outcomes for a highly marginalized community, highlights how over-reliance on robust statistical metrics can overshadow the value of approaches that may be better suited to address barriers for those most in need. This also exemplifies a dynamic where power is continuously held by institutions, many of which are predominately White academic institutions, that are well-resourced enough to offer the rigor necessary for EB/EI evaluation. Ultimately, this reinforces their ability to secure additional funding and continuing leading the development of EB/EI approaches, despite sometimes recycling well-known interventions under the guise of “innovation”.Similarly, the concept of “expertise” becomes of particular importance. Although emphasis on clinical expertise and experience is crucial, it is also important to further deconstruct how expertise was defined in the coordination of CIE’s expert panel and how this may have introduced biases into the decision-making process. The evidence rubric developed by Northwestern University considered the ways interventions addressed bias through their design and analytic methods. Yet, no effort was made to address implicit bias amongst expert panel members when prioritizing interventions for the final CIE compendium. Characteristics such as a patient’s race, ethnicity, gender, drug use, socioeconomic status, and HIV/AIDS status have been highlighted as issues that contribute to biases among healthcare professionals in the U.S., and evidence has shown that physicians and nurses manifest implicit bias to a similar degree as the general population , 26. TheThe marriage between subjective clinical expertise, high-quality external evidence, and subjective community expertise functions as a strong foundation through which public health can explore innovation by expanding its approach to EB/EI science beyond a steadfast dedication to “conventional” research and evaluation frameworks. For example, the CIE evidence rubric may have benefited from weighing certain aspects of a study design or quality  differently if the study focused on a historically marginalized group, reported positive quantitative outcomes, and included quality qualitative data that supported the impact of the intervention even if it did not meet traditional statistical thresholds. This would have prioritized interventions that showed positive community impact through a variety of data points rather than focusing solely on improvements based on a numerical value. Reexamining evidence criteria may require relinquishing traditional structures constituting the creation and use of EB/EI practices, such that they would depend on a wider range of cultural parameters rather than relying solely on the expertise of the clinician and predefined statistical thresholds , 28. Alli.Acknowledge and Mitigate Privilege and Power: Researchers and funding entities engaged in EB/EI model development and implementation should analyze their work within the lens of privilege, White supremacy, and existing power hierarchies. Acknowledge that traditional research avenues utilized to develop, implement, and evaluate interventions for PLWH remain largely inaccessible and often exclude Black, Indigenous and People of Color (BIPOC) who can help reimagine ineffective and inequitable systems. This requires asking key questions to ensure privilege and power are acknowledged and addressed throughout each step of the research process. Some questions to consider include . That said, it will also be crucial to look beyond academic equity frameworks to truly prioritize community knowledge and agency. This means allowing space for a reframing of expertise to ensure those with lived experience are seen as valuable leaders in the research process rather than passive contributors. It will also require approaching each stage of the EB/EI development and implementation process with a critical eye for power, privilege, and the historical dynamics that exist between the different entities engaged. HIV research innovation offers an opportunity to not only highlight the structures that continue to hinder progress and reinforce inequities in care and prevention outcomes but to break the cycles that keep these structures alive.


In an effort to support best practices, medical associations often develop clinicalpractice guidelines. This can come with significant drawbacks. Due to professionaland scientific issues coming to light after publication, in 2019 the EuropeanSociety of Cardiology (ESC) and the European Association for Cardiothoracic Surgery(EACTS) recalled their recent 2018 clinical guidelines for treatment of left maincoronary artery stenosis.3 and theNational Institute for Clinical Excellence (NICE). Here association guidelines promote the use of transcatheter aortic valveimplantation as an equivalent to surgery, while NICE recommends surgery as afirst-line treatment. Thus, the same clinical evidence has led to substantiallydifferent recommendations.Recently we have seen a significant disparity between guideline recommendations onaortic valve stenosis from medical associations There is broad literature identifying the shortfalls of guidelines written byassociations, issues remaining largely unresolved. In this commentary, we provide aninsider’s view of these problems and suggest steps to address them. The overallprinciples for writing clinical guidelines (WHO and IOM) describe important areas for associations to address the most relevant being:management of conflicts of interests (COIs) and methodological transparency evidenceappraisal.These two issues have renewed concerns as to whether medical associations arereliable authors of clinical guidelines.7 Transparencyand full declaration of COIs, while necessary, are not sufficient to ensure bias isneutralised, as Goldberg has discussed persuasively.The inadequacy of managing organisational and personal duality of interests is alongstanding issue. Associations contribute to improving healthcare in the area ofnew technologies through educational meetings and training. Content expertise comeswith the advantage of clinical knowledge but it also brings diverse personal andcorporate COIs  which chThe large financial commitment in the development of new therapies requires thatcapital investments bring early returns, with short-term studies for therapiesindicated for long-term use a particular problem. Rapid decisions by regulatorspermitting early access to new technologies shift the responsibility for access tonew treatments to those who reimburse technologies; decision makers who often makeuse of association guidelines. Timely recommendations may then not be robust. Thisis how COIs may have led to the disparity in judging the limited evidence for therecommended treatment of aortic stenosis. Associations do not always accurately describe their ties with industry.Sometimes guideline funding is said to come from general funding (meaning it was notraised for the specific purpose of guideline production), and is often not described in detail. We suggest that associations shouldinclude details of individual industry relationships, including amounts and datesrather than consolidated under grouped financial income headings, as this level oftransparency will enable the reader to comprehend the context in which arecommendation is made.Medical associations and industry often enjoy a symbiotic relationship. Industrybenefits from clinical expertise and access to those who prescribe treatments, whilemedical associations benefit from financial support. Annual meetings for members areoften largely supported by industry, through the purchasing of sponsored educationalsessions and exhibition space, and the surplus is often the major source of for associations.There are other interests that can contribute to bias when writing guidelines, aslisted in 12 Theseoverlapping roles can lead to a lack of self-appreciation of bias, and, at worst,may lead to unsafe guideline recommendations, as occurred in the joint ESC-EACTSmyocardial revascularisation guidelines.13 An obvious and sometimesimplemented solution is for trialists not to play a role in codifying practice inguidelines, but this tends to lead to exclusion of the very people who know thestrengths and limitations of the evidence available. However, we believe that suchassessments are better accomplished with a significant input from specialists inevidence-based critical appraisal with no connections to the evidence beingappraised. The United States Preventive Services Task Force provides an example ofan independent volunteer panel of national experts who make recommendations based ona rigorous review of existing peer-reviewed evidence.It has become commonplace for content experts to play simultaneous and potentiallyconflicting roles first in the generation of evidence as trialists, second incodification of that evidence as guideline writers, and third as influentialofficials in medical associations playing a role in obtaining industry funding. Funding for the regularly updated ADA/EASD consensus reports onglucose-lowering management is also stated as coming from general organisationresources, but the associations' sources of support are not made clear.There is heterogenicity in the approach to dealing with COIs among differentorganisations. In diabetes, of particular note are guidelines from the AmericanDiabetes Association (ADA), European Association for the Study of Diabetes (EASD)and International Diabetes Federation. The ADA's annually updated Standards of Careare nominally funded from ‘general funds' without request for specific sponsorship,and the provenance of the writing is made clear.The three UK, European and global diabetes associations are all known to haverelationships with industry for guideline and conference activities, and allrecognise issues around individual experts having dualities of interests whenworking on guideline and consensus documents. However, this is handled by arequirement for transparency rather than exclusion of individuals either fromguideline groups or more particularly from chairing or being lead writer on suchactivities. Transparency may identify the potential for bias, but does notneutralise it. However, transparency in this manner may enable the implementation ofspecific strategies to address bias. For example, the chair of a guidelines groupcould be excluded if they are found to have financial conflicts above a specificmonetary value. There is a need to balance the potential for bias and expertise. Forexample, it may exclude too many with product knowledge if all potential guidelinesgroup members are required to have no COIs. This predetermined guidance on themanagement of conflicts within an organisation producing and disseminatingguidelines could also identify red flag areas where individuals with specificconflicts abstain from offering a judgement.The costs of cancer treatment are significant for healthcare and so are the financialinvestments in researching new therapies. Thus, oncology practice guidelines areimportant for optimising treatment and introducing new costly therapies. TheEuropean Society for Medical Oncology (ESMO) guidelines are used worldwide to guidetreatment decisions and assist healthcare payers in evaluating the benefit of newanti-cancer drugs. All authors must declare any potential COIs. A compliancecommittee verifies if COIs generate potential bias in the writing process.Activities and responsibilities of the committee include implementing and managingthe disclosure of interest policy, and overseeing background checks. However, the issues with non-financial COIs , includingthe panel chair, to be free of relevant industry relationships. The 2021 ESC-EACTS Guidelines for the management of valvular heart disease were written by 21 authors, of whom 18 declare one or more financial COIsreceiving unquantified income from industries whose products are included in the guidelines. Some authors declare owning shares orreceiving royalties. Non-financial COIs were not reported, and the associations didnot describe how these prevalent COIs were managed.It is not uncommon for ESC high-impact cardiovascular guidelines to be written andreviewed by members with significant and relevant industry financial ties.www.openpaymentsdata.cms.gov system, set up as a result of theSunshine Act, provides some degree of transparency and validation of the paymentsdeclared by industry to physicians, although physicians often under-declare their income. In Europe there is no mechanism to validate declared payments; such atransparent system is urgently needed despite barriers of cooperation betweencountries.In the USA, the The task of converting available clinical evidence into robust treatmentrecommendations is not straightforward. High-quality evidence from randomisedcontrolled trials (RCTs) is often unavailable, or when present, burdened withinternal validity challenges, such as bias in design, execution, statisticalanalysis and interpretation of results. Thus, guideline recommendations requirejudgement and subjectivity, an area where unconscious bias from COIs may haveadverse influence. A clear and reproducible process for guideline production shouldbe described and implemented, with the link between evidence and specific guidelinerecommendations made explicitly. We recommend that associations invest in designingand implementing suitable protocols which describe the entire process including: howmembers are recruited to the task; identifying roles and responsibilities; anddefining how evidence-based recommendations are derived. These steps should be partof formal standard operating procedures (SOPs) to ensure best internal practice.With regard to transparency of the process itself, we first recommend that all COIsof all members are described; this should include non-financial COIs as illustratedin  Associations should have pre-agreed procedures and guidelines on themanagement of COIs , which are known to introduce bias orperception of bias in the process and outcomes. When all COIs have been declared bypotential members of the committees, we recommend that an independent compliancecommittee decides eligibility and to what extent participation is allowed againstthe pre-agreed SOPs. However, finding a true independent compliance committee can bechallenging. It is important to recognise that the role of clinicians withsignificant COIs should be very limited, and they should be excluded from theprocess of shaping the final recommendations.While transparency about COIs and how they might influence guideline process is animportant step, we believe that most biases cannot be easily mitigated. in the process may be enhanced. This will add independent methodologicalcredibility and robustness, although presently their methodology struggles where theRCT evidence base is thin.While the input of clinical experts remains important, the discussions of theguideline groups should be reported by independent scientific ‘writers' in the firstinstance, and can then be used to derive recommendations for editing and approval byall members. The role of formal organisations, such as GRADE or Cochrane collaboration,An independent accreditation process might be implemented to rate the quality ofguidelines produced by associations against ‘defined best practice’. Medicaljournals should publish only guidelines that meet required standards. However,medical associations often own their medical journals and this might add furtherpressures and bias. Independent editors are not immune to the attractions ofguidelines to readers and citation rates. Associations should also establishopportunities for training participants in guideline development methodology a stepwhich will provide an investment in the future for members and will facilitate thenecessary change in culture.Medical associations must recognise the significant limitations of their currentapproaches and embrace the necessary changes. The steps described above will go along way to the enhancement of the trustworthiness of the guidelines ifimplemented.However, in our experience, even with a call for such reform, there are practicalchallenges about how to assure that proposed significant changes would in be adoptedand adhered to. Thus, short of professional associations no longer writing orsponsoring clinical guidelines, the challenges described may no-matter the specificreforms that are recommended, and perhaps implemented. Exemplars, such as TheConference on Harmonisation, have demonstrated how appropriate regulation canimprove the integrity of research conduct. Embracing appropriate external standardscould similarly lead to an improvement in the trustworthiness of guidelines.