To date there is no consensus about the optimal strategy for keeping clinical guidelines (CGs) up-to-date. The aims of this study were (1) to develop a continuous surveillance and updating strategy for CGs and (2) to test the strategy in a specific CG.The main steps were as follows: (1) recruiting members for the CG Updating Working Group, (2) mapping the CG, (3) identifying new evidence from the CG Updating Working Group, (4) designing and running restricted literature searches, (5) reviewing drugs and medical devices alerts, (6) screening and assessing the new evidence, (7) reviewing and, if necessary, modifying clinical questions and recommendations, and (8) updating the CG document.The Pregnancy CG Updating Working Group consisted of 29 members, including clinicians, patients and caregivers, and clinical guideline methodology experts. We selected 69 clinical questions (123 recommendations) from the “Assistance during pregnancy” section.For the first update cycle (32-month duration), 9710 references were identified. Of these, 318 were pertinent, 289 were relevant, and 55 were classified as potential key references. For the second and third update cycles (6-month duration each), 2160 and 2010 references were retrieved, respectively. The continuous surveillance and updating strategy has not yet been completely implemented.Further resources are needed in updating the CG field, both for implementing updating strategies and for developing methodological research. Clinical guidelines (CGs) are useful tools to help patients, health care providers, and policymakers make evidence-based decisions about health care. Consequently, they need to be updated in order to guarantee the validity of their recommendations.Several studies have assessed the time of validity of CGs and their recommendations (defined as “time between the publication of a CG and the identification of new relevant evidence”) –5. Data The updating of CGs is an iterative process that involves an explicit and systematic methodological approach for the identification and assessment of new evidence not included in the original CG , 8, 9. ITo date, there is no real consensus on the optimal strategy for updating CGs , 7, 10. To address the updating of CGs, the majority of CG developers support the concept of living CGs , generalIn order to address some of the challenges related with living CGs, this study aimed to (1) develop a continuous surveillance and updating strategy for CGs and (2) test the strategy in a specific CG.We conducted a cohort study of recommendations from the Assistance During Pregnancy and Puerperium CG included in the Spanish National Health System CG Programme .The strategy was developed based on published methodological research and the experience of the CG Updating Working Group technical team , 20, 21.Three different strategies were used to identify new evidence: (1) a questionnaire sent to the CG Updating Working Group, (2) a restricted literature search strategy, and (3) a revision of available drugs and medical devices alerts.The questionnaire sent to the CG Updating Working Group aimed to identify any new relevant evidence that could have an impact on the CG (questionnaire available from the authors upon request). The questionnaire covered the different areas of the CG including the scope, new potential aspects not included in the original version, or new relevant evidence assessing the effectiveness and safety of the interventions. The survey also included questions about other relevant factors such as changes in the relative importance of the outcomes, changes in the resource use and cost of the interventions, equity, acceptability, or feasibility issues that might have arisen since the publication of the CG. Information about on-going research studies was also sought in the survey.www.ncbi.nlm.nih.gov/pubmed/clinical). Search strategies by topic were also developed using a specific filter to identify studies on how patients and other stakeholders value health outcomes and economic studies [Restrictive literature search strategies were developed for each clinical question in MEDLINE (PubMed) following a validated methodology described elsewhere . In summ studies , 23.www.aemps.gob.es/en/home.htm).Finally, drugs and medical devices alerts published by the Spanish Agency for Medicines and Health Products were reviewed . The questionnaire included the clinical question, the recommendations, and the references considered pertinent in the first screening to that clinical question. If the reference was considered relevant for that particular question by the reviewer, then it was deemed necessary to assess if the reference could potentially trigger an update (key reference). If it was the case, it was necessary to explicitly state which part of the question and/or recommendations was affected .Clinical question to be reviewed: question with potential key references or with alertsValid clinical question: question without potential key references or without alertsNew clinical questionEach clinical question was classified in one of the following categories:Once the questions were classified, we planned to update them following a similar method used in the development of the original recommendations but taking into account the new evidence identified and the evidence used to develop the recommendations.Conducting the 13 processes was considered a one update cycle. The first update cycle included new evidence since the last search date in the CG development process up to the first search date in the CG surveillance process; subsequent update cycles were scheduled every 6 months .We performed a descriptive analysis of the data: literature search time periods, number of identified references, number of screened references, and number of classified references . We described narratively the steps achieved.All members of the Pregnancy CG Development Working Group were initially contacted (20 members). However, since only five agreed to participate in this study, 30 additional candidates were contacted. The Pregnancy CG Updating Working Group finally consisted of 29 members: (1) clinical team: three medical specialists in gynaecology and obstetrics, three medical specialists in family and community medicine, and three midwives; (2) patients and caregivers team: three patients or patient representatives; and (3) technical team: 17 CG methodologists.We identified 89 clinical questions and 201 recommendations in the Assistance During Pregnancy and Puerperium CG . We focuWe contacted a total of 13 members of the Pregnancy CG Updating Working Group for the baseline survey and received 11 responses (84.6% response rate). We developed one search strategy per clinical question , as well as topic searches for studies on patients’ values and preferences and for costs and resource use.We identified 26 recommendations  related to drugs or dietary supplements. We consulted drugs and medical devices alerts from the Spanish Agency for Medicines and Health Products, searching by CG as topic.For the first literature search cycle (32-month period), 9710 references were identified. Of these, the technical team classified 318 as pertinent, 289 as relevant, and 55 as potential key references (Table For the second and third literature search cycles (each a 6-month period), 2160 and 2010 references were retrieved, respectively . For the second and third update cycles 2160 and 2010 references were retrieved, respectively.The continuous surveillance and updating strategy has not yet been completely implemented due to budgetary constraints.Only one previous study, published in 2003, assessed a continuous surveillance and updating strategy for CGs, specifically for cancer guidelines. This approach included a continuous and exhaustive literature search strategy, evaluation of the newly found evidence, review and updating of recommendations, and dissemination of the new evidence and modified recommendations among stakeholders. Similarly to our experience, the authors of this study highlighted the considerable resources required .Other initiatives have ventured the implementation of new technologies to facilitate the CG updating process. One of them, called MAGIC (Making GRADE the Irresistible Choice) provides a publication platform where the main content of CGs can be disseminated. MAGIC also facilitates uploading modifications, including any potential updates, which would be available to users instantly . SimilarWe were able to retrieve, organise, and map the original documentation related to the development of the assessed CG, including the clinical questions, recommendations and references, original literature search strategies, evidence syntheses, and GRADE evidence profiles. We also adopted a systematic and continuous approach (every 6 months) to identify new evidence and to assess its impact on the CG recommendations. Lastly, we introduced evidence searches for patients’ values and preferences and for costs and resource use in the surveillance process.However, our work is subject to some limitations. First of all, we have not been able to assess the impact of the new evidence on clinical questions and recommendations for either the second or third update cycles. In addition, we have not reviewed or modified clinical questions and recommendations based on the identified new evidence in any of the update cycles.Second, we had difficulties assembling the Pregnancy CG Updating Working Group. The vast majority of the CG Developing Group did not take part in the implementation of the strategy. Hence, an almost new working group had to be set up for this purpose. On the other hand, some members of the Pregnancy CG Updating Working Group withdrew during the study, probably due to an excessive study-related workload .Third, the first surveillance cycle was quite resource-intensive  and required the retrieval, mapping, and classification of the documentation generated during the development of the original CG. The process was optimised in the subsequent update cycles (second and third) given that (1) the process had already started and (2) the time between cycles (6 months) and, consequently, the volume of references (approx. 2000 references) were smaller.Lastly, and related to the previous limitation, we did not have adequate funding to take on the management and development of the completely continuous surveillance and updating strategy we originally intended to implement. CG developers should consider using different surveillance and updating strategies to maintain their CGs up-to-date . More research is needed to identify which CGs, topics, or areas could benefit from this or other approaches.Implementing a continuous and restricted literature search process is a potentially feasible approach for the surveillance of new evidence. A continuous surveillance and updating strategy (as living CG) requires long-term substantial resources for its adoption. Further resources are needed in the updating CG field, both for implementing updating strategies and for developing methodological research.


To determine the association of Diopsys® NOVA-LX amplitude and latency abnormality scores with perimetric staging of chronic glaucoma, and to explore potential single-visit short-duration transient visual evoked potential (SD-tVEP) trend detection ability utilizing Humphrey 30-2 field progression data.Setting: Glaucoma subspecialty clinic. Participants: Treated adult chronic glaucoma patients undergoing SD-tVEP evaluation. Main outcome measures: (1) Proportion of eyes designated as suspect or abnormal by the NOVA-LX multifactorial algorithm were determined as a function of glaucoma severity using the most recent Humphrey visual field analyzer (HVFA) 30-2 field. (2) Association between long-term HVFA-guided progression analysis (GPA) annual slopes and SD-tVEP abnormality was assessed to determine whether a single VEP test might help to identify eyes more prone to progressive visual field (VF) loss.vs normal VEP latency was -0.87 ± 0.3 dB/year vs -0.32 ± 0.4 dB/year.One hundred and thirty-three eyes of 84 patients (mean age 68 years) were analyzed. The SD-tVEP abnormality increased proportionately with severity of VF loss under high-contrast (Hc) test conditions for both latency (p = 0.001) and amplitude (p < 0.01). The HVFA progression analysis printouts existed for 91 eyes (mean 12.3 fields per eye/range 5-18). Nearly three-quarters (72.5%) of eyes with mean annual HVFA progression >0.7 dB/year (n = 29) had single-visit VEP latency abnormalities. Fewer than half (46.7%) of the remainder (n = 62) showed latency abnormality. Mean progression for eyes with abnormal Diopsys NOVA-LX Hc latency abnormality shows strong association with VF loss among a diverse population of clinical patients undergoing active treatment for chronic glaucoma, and appears likely to afford clinically useful trend-detecting test.The SD-tVEP has the potential to serve as a single-visit clinical indicator to identify glaucoma patients at high risk for VF progression.How to cite this article: Trevino R, Sponsel WE, Majcher CE, Allen J, Rabin J. Association of Diopsys® Short-duration Transient Visual Evoked Potential Latency with Visual Field Progression in Chronic Glaucoma. J Curr Glaucoma Pract 2018;12(1):29-35. They also showed VEP latency prolongation was frequently abnormal in ocular hypertensives but not in control eyes. Recent technological developments have made VEP assessment faster, more reproducible, with interpretation of test results more objective, and have brought down the cost of the instrumentation. One such technological innovation is SD-tVEP. This process decreases test duration substantially by means of synchronized signal acquisition in combination with a postprocessing technique that provides less subjectivity in waveform assessment.8The VEP is an objective measure of visual function that assesses the electrical activity of the cerebral cortex using electrodes placed on the scalp, while the subject views standardized visual stimuli.9 have recently reported on the ability of SD-tVEP latency to objectively discriminate between normal and glaucomatous eyes. In this study, we endeavored to assess rates of abnormal SD-tVEP amplitude and latency findings in adults under therapy for chronic glaucoma using the Diopsys Nova-LX P100/N75-referenced Hc and low-contrast (Lc) stimuli, with the ultimate goal of determining the potential clinical value of single-visit SD-tVEP as a potential indicator of VF progression risk. Low-contrast testing demonstrates degradation of magnocellular pathways, and might be expected to help provide an early indication of glaucoma. High-contrast testing demonstrates degradation of parvocellular pathways and might be anticipated in glaucomatous eyes with or at risk for pericentral visual loss. Any dynamic neural function test able to demonstrate strong association with the presence of disease might have potential to help distinguish adequately treated eyes that are likely to remain stable from those that may progress despite apparently good intraocular pressure (IOP) control. A measure of signal intensity, VEP amplitude, should be reduced by both the absence of lost axons and inactivity of extant but dysfunctional axons. Conversely, VEP latency, a measure of conduction velocity, can only be affected by the state of intact neural pathways, since dead axons send no contributory signal to the occipital cortex. Thus, it is reasonable to anticipate that among a diverse clinical population receiving aggressive therapy, eyes with normal VEP latencies might be more likely to remain clinically stable and at lower risk of continued axonal loss, while those with significant latency delay might be more likely to continue to lose even more of their already depleted complement of axons. If so, appropriate adjustments of therapeutic intervention and follow-up rates for higher- and lower-risk patient subpopulations could decrease visual morbidity and save considerable time and expense. Visual fields and optical coherence tomography are great clinical assets for helping discern which eyes exhibit structural and functional damage, but neither modality can readily provide evidence based on single visit on which eyes might be more or less prone to progression until multiple studies have been performed. It may require 24 to 36 months of periodic follow-up assessment to verify mild-to-moderate VF progression or nerve fiber layer loss, during which time the adequacy of ongoing therapy is uncertain, and potentially preventable permanent axonal loss is allowed to progress.Pillai et al5 Reliability and pathologic indices are automatically assessed by the device, in analogous manner to those generated by familiar tomographic and perimetric devices in widespread clinical use. Stimulus luminance, contrast, size, electrode placement, filter settings, and the normative database employed by the system are all standardized. Quantitative numerical amplitude or latency values are used to generate pathological indices using a proprietary software algorithm. A reliability index is generated based on waveform structure and artifact detection by the software system.Approximately 2000 Diopsys units are in present use in the United States and Canada . These devices utilize a standardized protocol outlined previously.The objective of this study is to evaluate the potential clinical utility of this commercially available test as administered by trained ophthalmic technicians under manufacturer recommended conditions using the current version of the standardized NOVA-LX semi-automated protocol in the evaluation and monitoring of patients with chronic glaucoma. It is important to emphasize that this is not an electrophysiological study intended to explore the strengths and weaknesses of SD-tVEP methodology. It is a strictly practical assessment of a new and now widely used commercial product simplified for practicing clinicians very familiar with the intellectual challenges of integrating multiple imperfectly measured physiologic risk factors into their decision-making for patients with glaucoma.® system between August 2013 and April 2014 at a single ophthalmology glaucoma specialty practice  were reviewed. All examinations were performed using a fixed protocol in the same clinical setting by qualified ophthalmic technicians who underwent formal training with the system but with no prior experience in electro-physiologic testing. All eyes had been undergoing therapy with what was deemed to be appropriately aggressive therapy , and IOPs were thus generally well controlled among all the eyes evaluated in this study .This cross-sectional protocol was provided an official noninvasive study waiver by the Institutional Review Board of Baptist Health System and the Institutional Review Board of the University of the Incarnate Word, and adhered to the tenets of the Declaration of Helsinki. All data were managed in accordance with the regulations set forth in the Health Insurance Portability and Accountability Act. Clinical records of adults with chronic glaucoma who underwent SD-tVEP evaluation with the Diopsys NOVA LX5 and are briefly summarized here. The subject is positioned 1 meter from the 17 inch video monitor. All testing is performed monocularly with the subject corrected for the 1 meter working distance. The Diopsys NOVA-VEP uses a three-electrode setup. The active electrode is attached to the scalp at 0z , the reference electrode is placed on Fz (on the center of the patient’s forehead), and the ground electrode is placed on Fp1 (on one side of the patient’s forehead just above the temple as close to the hairline as possible). The stimulus is a 32 × 32 checkerboard pattern that reverses at a rate of 1 Hz . The examination sequence consists of an 8-second warm-up period followed by 15 seconds with a 10% contrast (Lc) target, and finally 15 seconds with an 85% contrast (Hc) target. Each stage of the examination may be repeated if the patient was not attending to the stimulus during the examination. The fellow eye is then tested in an identical manner.Details regarding the Diopsys VEP protocol have been published elsewhere,For each eye, after the amplitudes and latencies of the SD-tVEP under both Lc and Hc stimuli conditions were collected, the VEP findings were interpreted by the Diopsys device’s intrinsic first-generation software as being normal, suspect, or abnormal. For patients with more than one VEP examination in their record, data from the exam in closest proximity to their most recent VF was collected. The mean deviation (MD) of the most recent Humphrey 30-2 SITA-standard VF was then used to stage the severity of the glaucoma as being mild (MD > -6.00 dB), moderate (-6.00 dB ≥ MD > -12.00 dB), or severe (MD ≤ -12.00 dB). Finally, the progression of VF change over the preceding 3 to 7 years for each subject was determined using HVFA intrinsic GPA software on all subjects who had previously undergone at least five reliable VFs that generated an automated printout. The mean Visual Function Index percentage VF survival status for each eye was recorded as the midpoint value for the established linear progression.For inclusion in the study, patients were required to be over 18 years of age at the time of their examination and carry a diagnosis of chronic glaucoma. Patients with all forms of chronic glaucoma were eligible for inclusion, including open-angle, narrow-angle, stabilized uveitic, posttraumatic, and congenital glaucoma. Because we are not aware of any reported differences in electrophysi-ologic defects occurring among the various subtypes of chronic glaucoma, we included patients with all forms of chronic glaucoma in this analysis. Patients with ocular comorbidities that could confound VF interpretation, such as dense cataract or advanced maculopathy were excluded. Only clinical records containing a complete data set were included in the final analysis. A complete data set consisted of (1) SD-tVEP examination using both Lc and Hc targets each containing a P100 wave that was identified and interpreted by the device as normal or abnormal; and (2) a reliable Humphrey 30-2 automated perimetry examination  performed within 6 months of the VEP examination.The unit of analysis for this study was each eye of a patient that met the inclusion criteria. Both eyes of a patient with bilateral glaucoma were included if they both met the inclusion criteria. Amplitude and latency data were tabulated for each eye. Any interpretation other than ‘normal’ for each parameter was categorized as ‘abnormal.’ This included both red  and yellow (borderline) coded results in the Diopsys VEP histogram report. For the comparisons of latency with VF progression, the absence of a numerical latency value in eyes capable of generating a waveform acceptable for automated amplitude analysis was also deemed to be an abnormal latency result. The MD of the HVFA automated perimetry exam performed at or closest to the date of the VEP examination was recorded and used to stage the severity of the glaucoma as follows—mild: MD > -6.00 dB; moderate: -6.00 dB ≥ MD > -12.00 dB; severe: MD ≤ -12.00 dB. Probability values are reported for differences attaining statistical significance <0.05. Single-factor analysis of variance was used to test for VEP differences between staged groups, and two-tailed t-tests were used to identify differences between the Hc and Lc amplitude and latency testing responses. The McNemar chi-square test was used to compare rates of abnormality of the P100 latency and amplitude under Lc and Hc test conditions within each staged group. Mantel-Haenszel linear-by-linear association analysis was used to test for trend in abnormality rates across staged groups. All statistical analyses were performed using Statistical Package for the Social Sciences Statistics version 21 .A total of 88 patients underwent SD-tVEP examination during the study period . Of these, four were excluded because complete data were not available for either eye. Of the remaining 84 patients , 49 (58%) had complete data available for both eyes and 35 (42%) had complete data for one eye only. Of the 35 patients with data available for one eye only, 28 (80%) had only one eye with sufficient visual function to undergo testing. The remaining 7 (20%) had undergone testing of both eyes but the Diopsys device was unable to interpret either the amplitude or latency of the waveform under Hc, Lc, or both test conditions in the fellow eye. Hence, our total study sample consisted of 133 eyes . Of thesAmong the 71 eyes with mild VF loss (mean MD: -1.19 dB), latency abnormalities occurred more frequently than amplitude abnormalities. This difference was not statistically significant under Lc conditions, but achieved statistical significance under Hc conditions (p < 0.01). The VEP abnormalities occurred more often using Hc targets than Lc targets, but this difference did not achieve statistical significance for either amplitude or latency parameters.vs Lc latency and Hc latency vs Lc latency).Of the 20 eyes with moderate VF loss (mean MD: -9.12 dB), none demonstrated an amplitude abnormality under Hc test conditions, and only one had an amplitude abnormality under Lc conditions. The absence of any Hc amplitude abnormalities in this group prevented us from performing McNemar analysis on this VEP parameter. There was no significant difference in the prevalence of other VEP parameter abnormalities (Lc amplitude Among the 42 eyes with severe VF loss (mean MD: -19.77), VEP abnormalities occurred significantly more often using Hc targets than Lc targets , and latency defects were significantly more common than amplitude defects under both Lc and Hc conditions .There was a clear trend of greater prevalence of VEP abnormality using the Diopsys scoring algorithm with increasing severity of VF loss . This asIn view of the relative strength of these associations of latency abnormality with VF status, latency abnormality (Hc and/or Lc) was the comparative indicator we then used to explore the most recent HVFA GPA printouts among our study population for any potential association between VF progression and SD-tVEP . Ninety-13 No single test can detect all glaucoma, in part because of the diverse character of the many pathologic subtypes that exist. Observable relationships between VF loss and nerve fiber loss have become much clearer over the past two decades as computerized perimetry and tomographic methods have simultaneously advanced. Indeed, such refinements have helped confirm the coordinating role played by the central nervous system in the bilateral progression of chronic glaucoma.14 Future therapeutic advances will require a further delineation of glaucoma-tous subtypes, based on traditional clinical evaluation alongside complimentary genetic and neurophysiologic findings. One key to this etiologic delineation will be to determine whether a particular individual’s visual deficit is a consequence of intraretinal dysfunction, visual pathway compromise, or both. While both VEP and electroretinogram (ERG) can now be conducted with the Diopsys system, at the time of this study only the SD-tVEP modality was conducted, which provided a standardized intrinsic scoring algorithm allowing for objective clinical comparison with VF status. The newly introduced, similarly standardized scoring algorithm for the Diopsys ERG modality should facilitate future clinical characterization of etiologic subtypes of chronic glaucoma based on both electrophysiologic modalities.The glaucomas, collectively, are a composite of ocular neurodegenerative conditions with the common features of axonal and VF loss. Historically, associations between clinically measured risk variables  have been surprisingly weak.5 who found greater SD-tVEP latency in individual subjects in the eye with greater field loss. Pillai et al9 also found a significant correlation between SD-tVEP latency and severity of glaucomatous VF loss, but among their population Lc latency was more strongly correlated with perimetric staging of severity, which may reflect differences in patient populations including glaucoma type, age, gender, and/or racial differences. Recently, Kothari et al15 utilized a conventional Hc VEP system and showed significant correlations between both Hc latency and amplitude and VF pattern standard deviation. Giving full respect to all these studies, we chose to characterize any latency failure, Lc or Hc, as the basis for comparison with VF progression among our study cohort to provide a simple primary algorithm that might be generally clinically applicable.In this study of VEP, we found that both Lc and Hc latency abnormalities were associated with VF mean defect, but SD-tVEP Hc latency abnormality was consistently and significantly more preponderant in each VF scoring category than Lc latency abnormality. Indeed, Hc latency abnormality was more prevalent than Lc latency abnormality at all severity stages using this instrument’s proprietary algorithm among our study population. Our latency results are comparable to those of Prata et al5 who used a similar system to compare fellow eyes of patients with asymmetric glaucoma and found that SD-tVEP amplitude was decreased in eyes with greater glaucomatous VF loss. This may be because their comparisons were within subjects, eliminating the great variability that exists between subjects.1 Earlier studies using conventional VEPs also reported correlations between glaucoma severity and VEP ampli-tude.16 Because VEP test results are specific to stimulus characteristics, such as check size, reversal rate, as well as display luminance and contrast, differences in test conditions may account for some of these observed differences. The pass/fail criteria for Diopsys SD-tVEP amplitude for glaucomatous eyes under active therapy may need to be refined, but the fact that a very high proportion of eyes produced amplitude values sufficiently robust to allow for automated latency analyses may be considered an advantage in the present context.In contrast to latency, we found that SD-tVEP amplitude abnormality occurred relatively infrequently, even in patients with severe VF loss. These results contrast with the findings of Prata et al17 As mentioned previously, unlike amplitude, latency has the potential to help monitor the functional well-being of the surviving functional axons whether they be plentiful or depleted in number. The incremental but strongly proportionate association of latency deficit with VF status among these actively treated eyes thus suggests that our ability to therapeutically normalize axonal conduction rates was directly related to the severity of the disease. This relationship was reflected further by comparisons with long-term VF progression, which indicate that SD-tVEP may afford incremental value as an elective single-visit trend-detection test of dynamic neural function.Given the very recent introduction of this patient-friendly electrophysiologic technology into the clinical setting, the associations observed between SD-tVEP latency and VF status compare favorably with the associations seen at a similar developmental stage with automated perimetry and nerve fiber layer analysis.In conclusion, Diopsys NOVA-LX® SD-tVEP amplitude and latency abnormalities were significantly associated with VF staging under Hc stimulus conditions. The presence of an SD-tVEP latency deficit was associated with long-term VF progression. The rapidity and clinical ease of the NOVA-LX protocol already allows for more immediate and widespread application of electrophysiology in the clinical realm, but its full potential as a diagnostic, monitoring, and trend-detecting tool for glaucoma management can only be fully realized with continued detailed study and refinement by multiple investigators, in much the same tradition as automated perimetry and computerized tomography.24 the informational yield of this first-generation Diopsys SD-tVEP automated analysis system is noteworthy. De Moraes et al23 recently confirmed disk hemorrhage as ‘the single most significant predictor for VF progression.’ Over an 8-year follow-up, Medeiros et al22 determined the relative rates for VF progression for eyes with and without disk hemorrhages was -0.88%/year vs -0.38%/year, a ratio remarkably similar to those reported here for VEP latency abnormality. The key difference is that disk hemorrhages in Medeiros’ meticulous study arose spontaneously in only 2% of glaucomatous eyes per year. On the contrary, SD-tVEP may be performed electively in the clinic on almost any glaucoma patient at any time.What is the actual clinical value of this kind of incremental informational yield? Considered in context of disk hemorrhage, the only well-established single-visit clinical indicator predictive of VF loss,


HIV self-testing (HIVST) is becoming popular with policy makers and commissioners globally, with a key aim of expanding access through reducing barriers to testing for individuals at risk of HIV infection. HIV self-sampling (HIVSS) was available previously to self-testing but was confined mainly to the USA and the UK. It remains to be seen whether the momentum behind HIVST will also energise efforts to expand HIVSS. Recent years have seen a rapid growth in the type of evidence related to these interventions as well as several systematic reviews. The vast majority of this evidence relates to acceptability as well as values and preferences, although new types of evidence are emerging. This systematic map aims to consolidate all emerging evidence related to HIVST and HIVSS to respond to this rapidly changing area.We will systematically search databases and the abstracts of five conferences from 2006 to the present date, with monthly-automated database searches. Searches will combine key terms relating to HIV  with terms related to self-testing . Abstracts will be reviewed against inclusion criteria in duplicate. Data will be manually extracted through a standard form and then entered to an open access relational map (HIVST.org). When new and sufficient evidence emerges which addresses existing knowledge gaps, we will complete a review on a relevant topic.This innovative approach will allow rapid cataloguing, documenting and dissemination of new evidence and key findings as they emerge into the public domain.This protocol has not been registered with PROSPERO as they do not register systematic maps.The online version of this article (doi:10.1186/s13643-017-0452-4) contains supplementary material, which is available to authorized users. HIV self-testing (HIVST) as an intervention and a potential HIV prevention tool is gaining popularity amongst policy makers globally, as well as amongst key populations affected by HIV. While previously HIVST was uncommon and generally confined to individuals working in healthcare settings informally testing themselves , changesIn some settings, HIV self-sampling (HIVSS) gained popularity before HIVST became available . HIVSS wThe development of and wide availability of low-cost rapid diagnostic tests (RDTs) have also made it possible to expand testing within and beyond facilities by using community-based approaches, which are increasingly used in HIV testing in low-, middle- and high-income settings , 4. The HIVST in particular is now considered to have an important role as part of the expansion of standard HIV testing services and is congruent with widespread shifts in western health systems which increasingly emphasise patient self-management and autonomy .The last 5 years have seen a rapid emergence of published data and corresponding reviews synthesising evidence around HIVSS and HIVST –13. ReflSince 2013, there has been an increasing flow of evidence about self-sampling and self-testing from a wider range of countries including Australia –16, BrazThe vast majority of this research, and hence the focus of all the reviews, has been the acceptability of HIVST, HIVSS and the values and preferences that inform the responses of key populations  to these emerging technologies. There can be little doubt that many individuals find the notion of HIVST to be acceptable and that it is feasible to deliver HIVST services in a range of settings in high-income countries. To quote the most recent, , “in genRecognising that the limited evidence base had already been repeatedly reviewed, we will undertake a systematic mapping exercise to formalise the literature searching process behind HIVST.org, an online centre for public health research, documentation and policies regarding HIV self-testing. A redesign of this website will create a searchable relational database where all literature on HIVSS and HIVST globally can be consolidated.Systematic mapping is a process of collecting, collating and describing the parameters of the existing literature on a particular topic . This syThe aim of this paper is to consolidate emerging evidence related to HIVST and HIVSS.To monitor and catalogue changes in published evidence as it emergesTo collate evidence describing social and contextual factors shaping HIV testing practices, especially barriers to testing, perceptions of the acceptability of self-testing and self-sampling relative to other testing approaches and associated issues including management of psychological effects and subsequent pathways to careTo document impacts from the expansion of HIVST as the technology continues to gain popularityThe Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) were used to prepare this protocol [see Additional file Published studies will be captured through a variety of standard searches which were trialled and refined throughout January 2016. Going forward searches will be automated to provide updates on the first of every month. This will enable us to capture all new articles published in that month and monitor changes in the published literature in real time. Searches will cover from January 1, 2006, to the present date, reflecting changes in the nature of HIV infection following widespread availability of anti-retroviral therapy and the emerging imperative to expand HIV testing , 37.Databases included in this search are MEDLINE, Embase, Global Health, Social Policy and Practice, PsycINFO, Health Management Information Consortium, EBSCO CINAHL Plus, Cochrane Library and Web of Science. Searches will combine key terms relating to HIV  with terms related to self-testing . Five HIV conference databases  will be systematically searched from January 2006 to the present date and then searched again annually as they become available. Additional grey literature search was not conducted. For full outline of database search strategy, see Additional file This systematic map will include peer-reviewed publications from a wide range of disciplines within social science and public health including epidemiology, sociology, anthropology, health economics and clinical practice. All study designs will be included. Examples include trials, observational data, economic evaluation and systematic reviews. Trials will include RCTs, cohort and other large-scale studies as well as smaller scale implementation, feasibility and demonstration projects. Observational studies will encompass quantitative epidemiological studies and cross-sectional studies of all types including qualitative, quantitative and mixed methods studies. Diagnostic accuracy studies will be coded as observational studies. Modelling will be included under the tag of economic evaluation. Systematic reviews and meta-analyses will be included.Comments, reviews that are not systematic, opinion pieces and letters to the editor will be excluded Table .Table 1SStudies written in English and published after January 1, 2006, will be eligible for inclusion in this map. Grey literature beyond conference papers and abstracts will not be included as this map focuses on academic outputs which have been through peer-review processes.Eppi-Reviewer 4 will be used as a reference reviewing and management software for the duration of the project. Using this software, the titles and abstracts of studies only will be screened in duplicate against inclusion criteria by researchers from the study team and coded as EITHER eligible for inclusion OR ineligible, or THEY will be put forward for A second opinion. If it is not possible to ascertain whether a study is eligible based on title and abstract, it will be coded as requiring a second opinion and the full text will be obtained. Results from both researchers will be reconciled. Where disagreements exist, these will be resolved by full-text screening by both researchers. If disagreement persists, a third member of the study team will undertake a full-text review and provide an opinion.Evidence related to HIVST and HIVSS will be input into HIVST.org, a resource which consolidates and maps evidence and policy globally. Following further development, HIVST.org will become a public facing, open access relational database for policy makers, practitioners and academics to search for up to date information on HIVST. Results will be displayed on a map and through a searchable database. This will be completed through the following steps:Studies which are eligible for inclusion will be coded by study design, population, year of publication, HIVST type and approach in EPPI-Reviewer 4. Following this coding, all studies will undergo a data extraction process, whereby key data are extracted and input into a Google document spreadsheet with pre-defined fields which link with those of a publicly available systematic map. This will be conducted by either a member of Sigma Research or a team member at the HIV Unit at the WHO. Data extraction will be done from full text where available, with abstract utilised when manuscripts cannot be sourced. Data extracted will include region, target population, aims, date of research, research methodology, study design, sample size, key results and summary of findings. Extraction for each study will be conducted by one member of the team only. See Additional file The Google document spreadsheet will then be uploaded into the relational map. The externally facing map will have filterability as a database from the public facing end, with broad meta-level tags for study design as well as more specific tags for population, setting, HIVST type and key themes to allow for easy retrieval of results. This will enable identification of studies by key theme and easy comparison and interpretation of results. The Google document spreadsheet which the data is input through will have greater filtering capability, but these will only be available to the study team.During the systematic mapping process, we do not plan to undertake a formal quality appraisal of studies. The key purpose of such a process is to explore the existence and characteristics of the evidence base of a topic rather than to make judgements about the quality of studies themselves . When syA key outcome of this systematic map will be the ongoing population of HIVST.org with results. Further, when sufficient evidence that is significantly different from the already published reviews emerges, then a systematic review can be completed from the subset of literature that is relevant to that specific research question.It remains to be seen when sufficient evidence will emerge concerning use and effectiveness of HIVST (and HIVSS), but the systematic mapping exercise will facilitate the refining of additional or alternate questions for a systematic review. The suitability of conducting a further review will be assessed qualitatively through identifying emerging trends in the published literature and in conjunction with experts at the WHO. Having pre-completed, screening processes will allow for a timelier compilation of a systematic review when it is relevant to undertake one.The precise approach taken for systematic reviewing  will be determined by what is most appropriate given the research question selected and the scope and quality of the pertinent evidence base.This open access rapid systematic map will enable easy access to up-to-date information for policy makers, practitioners, academics and others with an interest in HIVST. It will also formalise a current WHO endeavour and provide a greater degree of rigour to HIVST.org. Further, having searches and filtering already completed will allow for a more rapid completion of a systematic review on a relevant topic when the necessary data emerges.The approach outlined in this protocol has key strengths and limitations.The ability to rapidly capture and characterise emerging literature which can then be used for a variety of application for academics and policy makers is a key strength. The transparent process through which this is completed provides intellectual rigour. This approach also allows for easy contextualisation of results from individual studies amongst the diverse evidence base of HIVST and HIVSS.The major limitation of this type of review is that quality of evidence is not assessed. This rapid systematic mapping therefore gives all results equal weight in terms of prominence, and lower quality studies are not distinguished from those conducted with more rigour. It is therefore up to the audience to critically appraise the evidence base themselves.Additional file 1:PRISMA checklist. (PDF 130 kb)Additional file 2:Search strategy. Searches updated after peer review. (DOCX 19 kb)Additional file 3:Data extraction template. Template to be used to extract data and upload to map. (XLSX 9 kb)


Variability in neuronal response latency has been typically considered caused by random noise. Previous studies of single cells and large neuronal populations have shown that the temporal variability tends to increase along the visual pathway. Inspired by these previous studies, we hypothesized that functional areas at later stages in the visual pathway of face processing would have larger variability in the response latency. To test this hypothesis, we used magnetoencephalographic data collected when subjects were presented with images of human faces. Faces are known to elicit a sequence of activity from the primary visual cortex to the fusiform gyrus. Our results revealed that the fusiform gyrus showed larger variability in the response latency compared to the calcarine fissure. Dynamic and spectral analyses of the latency variability indicated that the response latency in the fusiform gyrus was more variable than in the calcarine fissure between 70 ms and 200 ms after the stimulus onset and between 4 Hz and 40 Hz, respectively. The sequential processing of face information from the calcarine sulcus to the fusiform sulcus was more reliably detected based on sizes of the response variability than instants of the maximal response peaks. With two areas in the ventral visual pathway, we show that the variability in response latency across brain areas can be used to infer the sequence of cortical activity. The process of averaging effectively suppresses noise and increases the signal-to-noise ratio of the measurements. Because of averaging, response variability is often ignored.Neural variability in response latency is usually considered to be caused by random noise. Based on the assumption that the measurement at each trial consists of an invariant response waveform and uncorrelated noise2, reading4, online imitation of lip movements6, and somatosensory processing8. Peak latencies are typically defined as the interval between the stimulus onset and the time at which responses reach the maximal amplitude. However, measurements of peak latencies can be unstable and prone to noise contamination. Specifically, researchers have to decide to measure the latency of either positive or negative peaks, which may have similar magnitudes. Moreover, cortical responses may not always show clearly defined peaks. For example, multiple peaks are commonly present in the time courses in a given cortical area.The sequence of brain activity across areas has been typically inferred by the relative size of a specific feature of the evoked responses. Temporal features, such as onset or time-to-peak, have been widely used to estimate the progression of cortical activity. With magnetoencephalographic (MEG) measures, peak latencies from different cortical areas have been used to infer the sequence of activity. This strategy has been used to disclose sequential brain activity in studies of face perception11. It has also been reported that along the mammalian visual pathway, higher-order neurons, or neurons further away from sensory inputs, usually showed greater response variability in terms of spike timing13. The variability of neuronal responses could be due to noise from sensory or cellular levels, such as synaptic responses14. In addition, small amount of latency variability could accumulate as neural activity propagates or as information flows from lower to higher-level areas14. When large neuronal populations were recorded by non-invasive technique in healthy human brains, similar patterns of variability were found. For example, with a visuomotor task, Tang et al.15 found that the early MEG responses in the primary visual cortex showed smaller latency variability than the late responses.It has been shown that neural responses differ across trials when the identical stimulus is presented repeatedly: at the neuronal level, single-digit unit recordings suggested that neuronal responses to the identical visual stimuli varied considerably across trials in cat and monkey visual cortexBased on micro- and macro-scale neuronal findings in the visual cortex, we hypothesized that functional areas at later processing stages would have larger variability in response latency compared to areas at earlier processing stages. To test this hypothesis of increasing latency variability along the functional pathway, we examined if the size of regional latency variability would match the known sequence of cortical processing. Here, we used the ventral pathway of face processing to test this hypothesis.17. The M170 or N170 response has been consistently localized to the fusiform gyrus20. Moreover, MEG studies have reported sequential activity from the calcarine fissure to the fusiform gyrus. Specifically, face-related cortical activity was found in the calcarine fissure with peak latencies around 110 ms followed by activity in the fusiform gyrus with peak latencies around 170 ms using either dipole models17 or distributed source estimates21. Taken together, the consensus is that the primary visual cortex functions as the initial stage to process general visual information, followed by the fusiform gyrus, which is specifically responsive to face detection and categorization22.Face-selective event-related fields or potentials measured by MEG or EEG (M170 or N170) have been reported previouslyBased on the previous findings of sequential visual processing from the primary visual cortex to the fusiform gyrus, the goal of our present study was to characterize the variability of response latency during face processing. We specifically examined the variability of response latency in the primary visual area  and the fusiform gyrus. Neural processing in these two areas was taken to reflect the sequence from lower-order primary sensory cortices to higher-order association areas. Using MEG measurements and based on our hypothesis, we expected that the variability of response latency in the calcarine fissure would be smaller than that in the fusiform gyrus. If true, the relative positions of cortical areas in the functional ventral pathway of face processing could be inferred by the size of response latency variability. Furthermore, we estimated the sequence of functional processing across brain areas in both the time and frequency domains by using dynamic and spectral decompositions of response latency variability. Dynamic estimates of response latency variability can reveal specific intervals of clear sequential processing, while spectral decomposition of response latency variability may disclose higher functional specificity as the neural activity at distinct oscillatory frequencies is related to different functions.Evoked responses to images of faces were observed in the calcarine fissure and fusiform gyrus in both the left and right hemispheres. Based on anatomically defined regions of interest Fig. , the grop = 0.024). No significant difference was found between the peak latency in the calcarine fissure and the left fusiform gyrus . As shown in Fig. p = 0.003), but not the right fusiform gyrus .To compare peak latencies in the fusiform gyrus and the calcarine fissure, Wilcoxon signed rank test was used. By identifying the maximum peak latency within the pre-defined time window 70 ms–200 ms) from the average waveform in each cortical area from each subject separately . Noise levels were also significantly higher in the right fusiform gyrus than the calcarine fissure  , nor between the right fusiform gyrus and the calcarine fissure  . Greater latency variability in the left fusiform gyrus compared to the calcarine fissure was found in 11 out of 14 subjects  across subjects.For the static estimates of latency variability, we calculated the standard deviation of relative latencies across bootstrap samples. This latency variability was estimated for each subject and each area separately. We found that when face images were presented, there was a trend of larger latency variability in the left fusiform gyrus (31.8 ms+/−16.1 ms) than the calcarine fissure . The right fusiform gyrus showed significantly larger response latency variability than the calcarine fissure between 70 ms and 200 ms (FDR p < 0.05).The latency variability was also estimated dynamically using a moving window approach. Dynamic estimates of latency variability are displayed in Fig. p = 0.403; calcarine < right fusiform, Z = −0.789, p = 0.430). Differences between the traditional measures and the dynamic measures were also not statistically significant .To evaluate the sensitivity of different measures, we compared the number of subjects showing consistent patterns across regions of interest in term of the maximum peak latency and latency variability Table . An earlp = 0.167).Percentages of subjects showing the above sequence of activity were also calculated. Averaging across the left and right fusiform gyrus, we found 68% of the tested subjects with earlier peak latencies in the calcarine fissure than the fusiform gyrus using the traditional measures of peak latency. Using the static estimates of latency variability, the percentage of subjects exhibiting smaller variability in the calcarine fissure compared to the fusiform gyrus was also 68%. Using the dynamic estimates of latency variability, 89% of the subjects showed smaller variability in the calcarine fissure compared to the fusiform gyrus. Overall, the dynamic estimates of latency variability showed a non-significant trend of higher sensitivity in detecting the specified sequence of activity, compared to the traditional measures of peak latency activity  significantly larger latency variability in the fusiform gyrus than the calcarine fissure between 70 to 130 ms and 170 to 180 ms in both hemispheres Fig. . In shorIn our study, ROIs included the primary visual cortex as the region responsible for early visual processing and the fusiform gyrus as the region responsible for later face detection and identification. From the static estimates of latency variability, we found the fusiform gyrus, an area responsive to faces, showed a trend of greater latency variability than the calcarine fissure Fig. .21. These previous studies identified the maximum amplitudes from the sensor data or source data estimated using dipole models or distributed source estimates. Therefore, results from the present study support our postulate that the variability in regional response latency can serve to identify the sequence of activity.While the static estimates of variability provide an overall measure of latency variability, the dynamic and spectral estimates of variability provide more temporally and spectrally specific analysis on latency variability by decomposing time series data into finer intervals and frequency bands. From the estimated latency variability in the temporal domain Fig. , we foun21. Nevertheless, several studies have also reported face-selective responses start as early as 100 ms28. Taken together, these findings suggest that differences in variability in this early latency range can be associated with extracting stimulus information required to categorize faces or non-faces.Specifically, in the dynamic estimates, significantly larger variability was found in the fusiform gyrus compared to the calcarine fissure in the time window between 70 and 130 ms and 170 to 180 ms after the stimulus onset in both hemispheres. This latency range appears to be earlier than the typically reported face-selective evoked response around 170 ms30. Hence, relatively large variability observed after 200 ms in our present study could indicate multiple sources of information exchange , whereas small latency variability could be related to a simpler pattern of information inputs . When comparing latency variability across regions, significantly larger latency variability was found in the fusiform gyrus than the calcarine fissure in the latency range between 70–200 ms, but not after 200 ms. This result could reflect feedforward inputs or bottom-up effects from the calcarine fissure to the fusiform gyrus before 200 ms. However, in latency ranges later than 200 ms, both the feedforward and feedback signals may work at the same time. We speculate that such bidirectional information flows between the calcarine fissure and the fusiform gyrus could account for our finding that there were no dominant directions of influence and no significant differences in latency variability between the calcarine and fusiform gyri.During the latency range between 70–200 ms, latency variability was relatively small compared to latency variability observed later than 200 ms. This pattern of response was observed in both the calcarine fissure and fusiform gyrus. Previous EEG studies have related increased signal variability to greater information transmissionOur results also indicate that dynamic measures of latency variability could be more sensitive than static measures of latency variability Table . By calc32 over posterior electrode positions. Using intracranial EEG, responses to faces were found in a wider frequency range, including the theta, alpha, beta, and gamma bands33. With MEG measures, significantly stronger responses in the right occipitotemporal area were reported between 4 and 25 Hz when comparing responses to faces and inverted faces34. These findings suggest that oscillatory activity across frequency bands could be associated with different aspects of face processing, such as information integration, face detection, or face identification. Taken together, the latency variability in frequency bands that have been associated with face processing is greater in the fusiform gyrus in both hemispheres than the calcarine fissure.In the spectral domain, significantly different variability was found between 4 and 40 Hz Fig. . Specifi14. The intra-subject variability examined in the present study also suggests the possibility of intervening processes in local processing. These intervening processes could include fluctuations in top-down processes of attention or degrees of task engagement. To further validate our hypothesis of increasing latency variability as information flows across cortical regions, future studies should be conducted to test whether latency shifts remain constant along different functional pathways, or increase as the cortical area gets more distant from primary sensory processing.The latency variability observed here can be attributed to intrinsic variability of neural processing, such as synaptic transmission or neurotransmitter functionsThe results from our present study indicate that there are no significant correlations between the static estimates of latency variability and the traditional measures of maximum peak latency Fig. . In addiOur results also reveal that peak latency might not be the optimal index to estimate the order of regional activity, particularly when the variability of regional response latency is large, as exemplified by our analysis Fig. . Averagi37. However, Granger causality assumes the time series should be stationary. This assumption is seriously challenged in evoked brain responses. For example, our dynamic estimates of variability indicate latency variability does not remain constant over time. It should be noted that while our approach does not require the stationary assumption and can be used to estimate the relative positions of regional processing in a functional pathway, we did not infer any causal influence across brain regions.One approach of detecting regional information flow is Granger causalityIn our analysis, the cross-correlation procedure requires a template waveform. Here, we used the averaged waveform across trials as the template. Because the template is defined for each subject and each ROI separately, variations between individuals do not exert influence in our analysis. However, variations within subjects or across trials still remains. Furthermore, our bootstrap samples were not single-trial responses, but averaged across a subsample of trials. The number of trials chosen to generate one bootstrap sample can affect our estimates of variability and the signal-to-noise ratio. We found that the sensitivity of detecting the specified sequence of activity across subjects was stable when using between 20 to 40 trials to form one bootstrap sample (see Supplementary Information for details). Cautions should be taken to determine the number of trials in generating the bootstrap samples in order to minimize the noise fluctuation and to detect the response variability at the same time.Using images of human faces to elicit neuromagnetic responses in brain areas subserving visual processing, we found that the order of brain areas demonstrating progressively larger response latency variability matched the expected sequence of information transfer across brain areas. Our present study suggests that regional response latency variability can provide meaningful information about the underlying sequence of neural processes. Differential variability between cortical areas can reflect their relative positions in a functional pathway. The close correspondence between temporal variability and the sequence of cortical activity in other functional processing pathways should be further tested with other complex stimuli and tasks.Fourteen subjects  participated in this study. All subjects provided written inform consent prior to participation and the experimental protocols were approved by the Institute of Review Board at the National Taiwan University Hospital. All experiments were carried out in accordance with the approved guidelines. All subjects had normal or corrected to normal vision.39 and the phase-scrambled versions of the same stimuli were presented randomly to subjects. Images of faces or scrambled faces were presented for 500 ms in duration with a random inter-stimulus interval ranging between 1800 and 2200 ms. Stimuli were presented using Presentation . To ensure that subjects were attending to the visual stimuli, subjects were instructed to press a button when two sequential images were identical. Four runs (about 9 minutes per run) of data were collected from each subject. About 200 trials of faces and scrambled faces were shown to each subject in each run.Visual stimuli of neutral faces from eight individuals41 was not used. Epochs with EOG exceeding 150 uV and MEG exceeding 3 pT/cm (gradiometers) and 4 pT (magnetometers) were removed from offline averages to suppress artifacts related to eye movements and system instability.MEG data were recorded using a 306-channel whole-head MEG system . MEG signals were band-pass filtered between 0.03–200 Hz and digitized at 1000 Hz. Temporal signal space separationT1-weighted structural images were collected . For visualization and localizing anatomical landmarks, cortical surfaces were reconstructed using FreeSurfer .Anatomical data were measured on a 3 T MR scanner  with a 32-channel head coil array. Three-dimensional 43 on the cortical surface. The MEG source spaces had about 7,000 vertices on each hemisphere. The forward models were calculated using Boundary Element Method (BEM) based on T1-weighted MRI data44. MEG noise covariance matrices were calculated using the 200 ms baseline prior to the stimulus presentation. Noise-normalized MNE, also called dynamic statistical parametric maps (dSPM)42, was calculated at each time point to map the extracranial MEG data onto cortical surfaces. Before averaging across subjects, source estimates from each individual subject were morphed to an average brain provided by FreeSurfer (subject “fsaverage”)46.MEG sources were estimated using anatomically constrained minimum-norm estimates (MNE)47. These four ROIs were the calcarine fissure and fusiform gyrus in the left and right hemispheres. In this study, the calcarine fissure is taken as the low-order visual area, processing sensory information before the information is sent to higher-level areas. The fusiform gyrus, part of the core system of face processing, is taken as the high-order visual areas for detecting and identifying faces48.Four regions of interest (ROIs) were defined by anatomical labels23, the maximum peak latency was defined as the time when the average response amplitude reached its maximum within the time intervals of interest. For example, the time intervals of interest were defined between +/−30 ms of the M100 responses in the calcarine fissure and M170 responses in the fusiform gyrus; that is, between 70 ms and 130 ms for the calcarine fissure and between 140 ms and 200 ms for the fusiform gyrus. However, these definitions already assumed an earlier response window for activity in the calcarine fissure compared to the fusiform gyrus. Defining the time windows of interest differently for the two regions of interest would defeat our purpose of identifying sequences of activity across regions. Thus, we used the same time window of interest for both ROIs. Our time window of interest was defined between 70 ms and 200 ms, wide enough to cover the activity in both the calcarine fissure and the fusiform gyrus.For comparisons, we also followed the conventional method of using peak latencies across regions to estimate the sequence of activity. In previous MEG studies when conditions of face and non-face were comparedTo estimate relative latency, we first calculated template waveforms separately for each subject in each ROI . The template waveform was obtained by averaging dSPM source waveforms across trials and across vertices within a given ROI. To cope with the low signal-to-noise ratio from single-epoch waveform, we estimated evoked responses using a bootstrap approach. Specifically, we obtained one bootstrap sample by randomly selecting 30 single-trial source estimates  and averaging over these trials. The bootstrap procedure was repeated 100 times for each condition, ROI, and subject. These responses were then low-pass filtered at 40 Hz.We also compared noise levels across ROIs. Noise levels were estimated by the standard deviation over the pre-stimulus or baseline period (−200 to 0 ms) and averaged across bootstrap samples and across subjects. To avoid potential confounds caused by regional differences in noise levels, we equalized noise levels across regions by adding Gaussian random noise (mean = 0 and standard deviation = differences in noise levels between regions) to the bootstrap samples across time.Then, we calculated cross-correlations between the template waveform and each bootstrap sample in each ROI. The template waveform was temporally shifted (−200 and +200 ms in steps of 10 ms). The shift corresponding to the maximum correlation coefficient was defined as the relative latency. With 100 relative latencies across bootstrap samples, we calculated intra-subject latency variability or the standard deviation of relative latencies across bootstrap samples. Intra-subject latency variability in the calcarine fissure and fusiform gyrus was compared using Wilcoxon signed-rank test.To further understand the relationship between the static estimates of latency variability and the traditional measures of peak latency, Pearson’s correlation coefficients were calculated between the static estimates of latency variability and the peak latency obtained using the traditional method as described in the previous section.49.Dynamic latency variability was calculated by first convolving the template waveform and each bootstrap sample with a Gaussian window with standard deviation of 30 ms. The window center was temporally shifted across the entire epoch, from 100 ms before the stimulus onset to 1000 ms after the stimulus onset in increments of 10 ms. Relative latencies were calculated using the same cross-correlation method as described above. Intra-subject latency variability was obtained by calculating the standard deviation of relative latencies across bootstrap samples within each time window. Within the pre-defined time intervals from 70 to 200 ms, the Wilcoxon signed-rank test was then used to compare intra-subject latency variability in the calcarine fissure and fusiform gyrus in each time window. Multiple tests over latency windows were controlled by the false discovery rate (FDR)To further compare the sensitivity of different measures , we counted the number of subjects showing a sequence of activity from the calcarine fissure to the fusiform gyrus from each measure. With the traditional measures of peak latency, a smaller peak latency in the calcarine fissure compared to the fusiform gyrus would suggest a sequence of activity from the calcarine fissure to the fusiform gyrus. With the static and dynamic estimates of latency variability, greater latency variability in the fusiform gyrus compared to the calcarine fissure would indicate a sequence of activity from the calcarine fissure to the fusiform gyrus. For the dynamic estimates of latency variability, the number of subjects showing the above sequence of activity was averaged across time windows and then rounded up or down to the nearest integer. To test whether the proportions or numbers of subjects differ between measures, Z-test was used.24 for the template and bootstrap samples. TSE was calculated by convolving time series data with a Morlet wavelet50 with width = 5. The center frequency of wavelet varied from 4 Hz to 40 Hz in steps of 1 Hz. The spectral power time series was then used for calculating relative latency and latency variability using the cross-correlation method described above. Intra-subject variability in latency between the calcarine fissure and the fusiform gyrus was compared using the Wilcoxon signed-rank test at each frequency. Multiple comparisons across frequencies were controlled by FDR49. All calculations were done using Matlab .In the frequency domain, latency variability was obtained by first calculating the Temporal Spectral Evolution (TSE)Supplementary Information


Electronic health  strategies are evolving making it important to have valid scales to assess eHealth and health literacy. Item response theory methods, such as the Rasch measurement model, are increasingly used for the psychometric evaluation of scales. This paper aims to examine the internal construct validity of an eHealth and health literacy scale using Rasch analysis in a population with moderate to high cardiovascular disease risk.The first 397 participants of the CONNECT study completed the electronic health Literacy Scale (eHEALS) and the Health Literacy Questionnaire (HLQ). Overall Rasch model fit as well as five key psychometric properties were analysed: unidimensionality, response thresholds, targeting, differential item functioning and internal consistency.2 = 54.8, p = 0.06), ordered response thresholds, reasonable targeting and good internal consistency (person separation index (PSI) 0.90). It did, however, appear to measure two constructs of eHealth literacy. The HLQ subscales  did not fit the Rasch model  and had suboptimal targeting for most subscales. Subscales 6 to 9 displayed disordered thresholds indicating participants had difficulty distinguishing between response options. All subscales did, nonetheless, demonstrate moderate to good internal consistency (PSI: 0.62–0.82).The eHEALS had good overall model fit . Whilst further studies are required to confirm this finding, it may be necessary for these constructs of the eHEALS to be scored separately. The nine HLQ subscales were shown to measure a single construct of health literacy. However, participants’ scores may not represent their actual level of ability, as distinction between response categories was unclear for the last four subscales. Reducing the response categories of these subscales may improve the ability of the HLQ to distinguish between different levels of health literacy. For patients to be able to optimally manage their health, they require an adequate level of understanding about their condition and associated management strategies –3. This Electronic health  literacy has become increasingly relevant in recent years with the development of eHealth tools to support healthcare delivery and management –9. HowevSeveral scales can be used to measure health literacy such as the Test of Functional Health Literacy in Adults (TOFHLA)  and the There is growing evidence to indicate that the Rasch measurement model, which measures a scale’s internal construct validity, is the gold standard for psychometric evaluations of outcome scales . Rasch aThe internal construct validity of the eHEALS and the HLQ was analysed using Rasch analysis in a population with moderate to high CVD risk. The first 397 consented participants in the CONNECT (Consumer Navigation of Electronic Cardiovascular Tools) Study  compriseDetails of the CONNECT Study have been published elsewhere . In brieThe eHEALS was used to assess eHealth literacy (Study 1). This scale aims to measure an individual’s perception of their knowledge and skills in relation to using electronic health information and determine whether an eHealth approach is suited to the individual ,26. It iThe HLQ was used to assess health literacy (Study 2). This scale aims to measure an individual’s capacity to effectively use health information and services . It is aThe Rasch model was used to examine the psychometric properties of the eHEALS and HLQ. Rasch analysis is a form of item response theory, where the ordinal ratings of the questionnaire are transformed to estimates of interval measures that demonstrate the essential features of the scale . Analysi2 statistic. A significant value (p<0.05) indicated that the observed data did not fit the expectations of the Rasch model [2 test is sensitive to sample size, with larger samples having a tendency to generate a significant value [The CONNECT data were analysed using IBM SPSS Statistics 22.0 , with the Rasch analysis completed using the RUMM2030 package using a partial credit model for polytomous data . Given that both the 8-item eHEALS and HLQ have multiple response category options (e.g. ‘strongly disagree’ to ‘strongly agree’), a partial credit Rasch model was used to examine the internal construct validity of both scales, which is not possible with, for example, a two-parameter logistic (2PL) model.  To deterch model . It is int value . Model fnt value ,33 as went value .Demographic characteristics of the 397 consenting participants are presented in 2 item-trait interaction statistic (p: 0.06) (The eHEALS met the Rasch model expectations as demonstrated by the χp: 0.06) . The scaWe found limited evidence to support unidimensionality of the eHEALS. Analysis using principal components analysis suggested that the eHEALS may be measuring two separate constructs of the eHealth literacy , which may indicate that items must be scored separately.Inspection of thresholds maps and category probability curves showed ordered thresholds for the five response categories (‘strongly disagree’ to ‘strongly agree’) used in the eHEALS scale, demonstrating that participants were able to distinguish between response options.The eHEALS scale displayed reasonable targeting (No significant DIF (or item bias) was evident in the eHEALS for age, gender, polypharmacy and education indicating no influence of these characteristics on response to any of the items of the scale.With a PSI of 0.90 , the sca2 item-trait interaction statistic <0.05). The remaining HLQ subscales did not reflect hierarchical ordering of the items across all levels of health literacy , displayed unidimensionality.Ordered thresholds were obtained for subscales 1 to 5 (‘strongly disagree’ to ‘strongly agree’). However, inspection of category probability curves for subscales 6 to 9 showed that participants had difficulty distinguishing between their response categories (‘cannot do’ to ‘quite easy’), as seen by the confluence of peaks in Targeting was suboptimal for all subscales of the HLQ (mean logit: 1.02 to 4.26) indicating the sample was slightly overqualified for the level of health literacy measured by the scale. This was further highlighted by the ceiling effect (Uniform DIF (p<0.05) was observed in HLQ subscales 2, 3, 4 and 8 for education, polypharmacy, gender and age, respectively. Subscale 3 displayed non-uniform DIF (p<0.05) for item 13 . However, in all cases, the DIF was not marked and isolated to one item per subscale with minor effect on each respective subscale.The PSI varied between 0.62 and 0.82 indicating moderate to good internal consistency for all nine HLQ subscales .This study found that the eHEALS had good overall fit to the Rasch model, distinct response categories, no item bias and reasonbale targeting. This provides evidence supporting the use of the 8-item eHEALS as a measure of eHealth literacy with higher scores truly representing higher levels of eHealth literacy. All subscales of the HLQ except for subscale 5, on the other hand, did not fit the Rasch measurement model and had suboptimal targeting. Nevertheless, all subscales apart from subscale 9 did demonstrate unidimensionality, had no major item bias and moderate to good internal consistency. This indicates that the HLQ suitably measures nine aspects of health literacy. Both scales were, however, unable to reflect mid to high ranges of health literacy. Consequently, when they are used to measure changes in ability over time, an individual would have to acquire a substantial increase in health or eHealth literacy for it to be reflected in their score. This could account for the presence of misfitting items and persons and highlights the potential for further scale testing and refinement.Prior studies using factor analysis or principal component analysis (PCA) and item response theory (IRT) have found the eHEALS to be internally consistent (Crohnbach α: 0.87 to 0.94) with modest to good stability ,17,34 anContrary to our findings, previous studies using classical test theory and item response theory  have supported unidimensionality of the eHEALS ,34. In oThe HLQ has previously been found to have a good level of construct validity and a composite reliability of ≥0.8 for almost all subscales ,36. HoweThis is the first study to have assessed and compared the internal construct validity of the eHEALS and the HLQ scales using Rasch analysis in a population with CVD. Validation of such scales is particularly important in order to accurately measure the health literacy of patients with chronic disease, such as CVD, who are active participants in the management of their health. This study was able to provide new insight into the measurement properties of two commonly used scales for eHealth and health literacy by comparing prior findings. It was also able to provide information regarding item bias (ie. DIF), which has not yet been examined in the eHEALS. Furthermore, Rasch was able to analyse several psychometric aspects of the scale, such as the hierarchical structure of items, ordering of response categories, DIF and the summation of the scale, which are beyond the scope of classical test theory. We were, therefore, able to highlight aspects of both scales which require further investigation such as whether the eHEALS measures two distinct constructs of eHealth literacy and provide further support for rescoring subscales six to nine of the HLQ response categories in order to better reflect hierarchical distribution of health literacy. Further validation is now required to test these changes in a different population.This research does have several limitations. Firstly, the cohort is mostly male and the group is known to have home Internet access, reducing generalizability of the findings. Secondly, both scales had many misfitting items and persons, which may in turn have contributed to the degree of misfit observed between the data and the Rasch measurement model. However, achieving model fit would have entailed deletion of items or persons, which was beyond the scope of this paper. Thirdly, this study did not seek to confirm whether individuals with higher eHealth or health literacy scores truly had better disease management. This is particularly noteworthy since a Dutch study found that perceived skills as measured by the eHEALS did not predict actual performance , althougElectronic resources are valuable tools to access health information, however, patients must acquire the skills to effectively engage with and benefit from the plethora of resources available online. This is particularly true for CVD in which disease management and prevention depend largely on patients’ health literacy. For healthcare providers to optimally assess a patient’s level of health literacy, valid and reliable scales are essential. This study demonstrates the good psychometric properties of eHEALS and highlights that the HLQ appropriately measures its nine distinct aspects of health literacy. Further research is now needed to determine the extent to which higher eHEALS scores correctly identify those individuals with greater eHealth capacities and whether collapsing response categories in the last four subscales of the HLQ improves boundaries between response categories.S1 Table(DOCX)Click here for additional data file.


Dirofilaria immitis is the causative agent of cardiopulmonary dirofilariosis in dogs and cats, and also infects humans. However, there has been no study on dirofilariasis in dogs in central China. From March 2015 to February 2016, sera from 1176 randomly selected household dogs from Henan province, central China were examined for D. immitis antigen using the Canine Heartworm Antigen Test Kit. The overall seroprevalence of D. immitis in dogs in Henan province was 13% (155/1176). The prevalence was significantly higher in older dogs and dogs kept outdoors, compared to the younger ones and those sheltered indoors. No significant difference of prevalence was observed between sexes. The results suggest that the risk of exposure to D. immitis in dogs is high in Henan, and prophylaxis against the parasite is advisable to decrease the incidence of canine dirofilariosis in this region.The heartworm  Dirofilaria immitis (heartworm), affects domestic dogs, cats, and various wild mammals, with increasing incidence in temperate and tropical areas [D. immitis worms can survive for seven years or more in dogs, usually producing chronic inflammatory vascular disease [The causative agent of cardiopulmonary dirofilariasis, al areas , 12, 16.al areas , 19. Adu disease .D. immitis infection in dogs from various countries, including Korea [D. immitis infection in dogs have been undertaken in different regions of China .2 and a population of approximately 106.01 million. Its geographical position is at east longitude 110°21′–116°39′ and at north latitude 31°23′–36°22′. The Yellow River passes through central Henan. The area has a continental monsoon climate, with four distinctive seasons. The average annual temperature is 12.1–15.7 °C, with a mean annual rainfall of 532.5–1380.6 mm. As shown in The study was conducted in Henan province, located in the central part of mainland China , and covD. immitis antigens.A total of 1176 blood samples of domestic dogs were collected from these five cities in Henan province between March 2015 and February 2016. Dog owners were asked for details of the animals’ age, sex, rearing condition, and medical history using a structured questionnaire. Blood samples were centrifuged and sera were recovered and transferred to 1.5 mL Eppendorf tubes. All sera were then stored at −80 °C until testing for circulating D. immitis infection, all serum samples were analyzed for the D. immitis antigens using the Canine Heartworm Antigen Test Kit  according to the manufacturer’s instructions. When testing samples from dogs with more than two adult female worms, sensitivities and specificities of this kit are 94% and 98% for D. immitis, respectively [In order to identify D. immitis prevalence in different variables were performed by the χ2-test. The differences were considered statistically significant if p < 0.05.Statistical analysis was performed using SPSS 20 software for Windows . Statistical analyses of D. immitis in dogs in Henan province, central China was 13.18% (155/1176). Compared with other provinces or cities in China, it was lower than the values of 51.6% in dogs in a study performed in Changchun [D. immitis among these regions may be due to differences in ecological and geographical factors, detection methods used, survey periods, sample sizes, and breed of dog populations in these areas. In the present study, the seroprevalence of D. immitis in males was 14.26% (88/617) and in females 11.99% (67/559) (p > 0.05). This is in agreement with previous studies [As shown in hangchun , 24.0% ihangchun , and 18.hangchun , similarhangchun , but highangchun , Guizhou8% 155/116. Comparhangchun . The dif67/559) . Althoug . AlthouD. immitis between dogs sheltered in different conditions [D. immitis infection in outdoor dogs (16.32%) was significantly higher than that in indoor dogs . A similar higher prevalence was also observed in outdoor dogs by Hou et al. [D. immitis infection in dogs increased significantly (p < 0.05) with the increase in age. The difference in prevalence with respect to age coincides with other studies where higher prevalence was observed in the adult group than in the juvenile one [D. immitis increases with age.A significant difference was observed in prevalence of nditions , 13. In nile one , 13, 15.D. immitis infection (13%) was found in domestic dogs in Henan, central China. Therefore, lifelong chemoprophylaxis is needed to prevent canine dirofilariosis. Monitoring the prevalence of this particular nematode among domesticated dogs is also important because it poses a serious health risk to humans.In conclusion, a high prevalence of The authors declare that they have no conflict of interest.


Sackett and colleagues first defined evidence-based medicine as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients”.Developing countries have multiple issues when it comes to evidence-based medicine. First of all, most of the evidence is imported. If we take all Arab countries as an example, their medical research production over an 18-year period is just 3% of the USA’s production.To improve the health care in our region of the world, we must invest majorly in our future doctors. Currently, our medical education focuses mainly on medical knowledge. However, because of the vast amount of medical literature published daily, we need to place much greater emphasis on evidence-based medicine. The transformation of research into practice should be a defined structured multistage process that every student or trainee is familiar with, otherwise confusion will reign due to imported medical literature and the eagerness of local physicians to copy the Western medical model.Our students should learn how to read the evidence. Critical appraisal is one of the most important skills we should teach our students and residents.  A crucial part of the critical appraisal process is whether the evidence is applicable in a particular setting. In addition to similarities in population and rates of illness, several other factors should be considered, e.g. nurse-to-patient ratio, the availability of other medical personnel and their skills level, the availability of devices, and very importantly the compatibility of the evidence with the society’s cultural beliefs and patient preferences.This article proposes a simple educational model for the transformation of the medical evidence from a published article into medical practice. It can be easily incorporated into the curriculums of courses designed for such purposes. It consists of three stages. The first stage (Publish stage) focuses on identifying the published research with the caliber to drive practice re-evaluation. Physicians should not revise their practice every time a new study is published. They should only do so in response to the publication of a large well-conducted study with major results or multiple studies with significant results reporting harm of a current practice or benefit of a new practice. General critical appraisal skills judging the quality of the evidence should be applied during this stage. The second stage  is primarily the preparation of the institution for the implementation of the new practice. This stage consists of reading the literature critically, evaluating its applicability locally, economically, and culturally, and subsequently adopting it if applicable. A working plan should be prepared that includes when the practice should start, the requirements needed for the practice on manpower, skills, and devices, and the first evaluation date. Distribution of the necessary knowledge in the form of lectures, posters, and workshops should then follow. Finally, any staff concerns should be addressed prior to introducing the practice. The third stage (Practice stage) is the initiation of the new practice with continuous evaluation. This includes reporting of unexpected mortality, major side effects, and staff confusion. It should also include a structured evaluation after completion of the predetermined period.Application of the proposed model has the potential to change our medical culture, especially in our region of the world where physicians are perceived as “up-to-date” based on their eagerness for any emerging evidence and their haste to change their practices. It is hoped that some of the wisdom and soul of medicine will be regained through the teaching of the Publish-READI-Practice model.I would like to thank Dr Eyad Altamimi for revising this manuscript.The author declares that she has no conflict of interest.