Scientific evidence is frequently offered to answer questions of fact in a court of law. DNA genotyping may link a suspect to a homicide. Receptor binding assays and behavioral toxicology may testify to the teratogenic effects of bug repellant. As for any use of science to inform fateful decisions, the immediate question raised is one of credibility: Is the evidence a product of valid methods? Are results accurate and reproducible? While the rigorous criteria of modern science seem a natural model for this evaluation, there are features unique to the courtroom that make the decision process scarcely recognizable by normal standards of scientific investigation. First, much science lies beyond the ken of those who must decide; outside “experts” must be called upon to advise. Second, questions of fact demand immediate resolution; decisions must be based on the science of the day. Third, in contrast to the generative adversarial process of scientific investigation, which yields successive approximations to the truth, the truth-seeking strategy of American courts is terminally adversarial, which risks fracturing knowledge along lines of discord. Wary of threats to credibility, courts have adopted formal rules for determining whether scientific testimony is trustworthy. Here, I consider the effectiveness of these rules and explore tension between the scientists’ ideal that momentous decisions should be based upon the highest standards of evidence and the practical reality that those standards are difficult to meet. Justice lies in carefully crafted compromise that benefits from robust bonds between science and law. Legislative and executive branches of our government routinely turn to scientific discoveries to guide the development of laws, policies, and regulations to serve and protect members of society. Similarly, our courts rely heavily upon scientific knowledge to make informed decisions about disputes over matters such as ownership, causality, and responsibility. In this essay, I focus on the role of science in courtroom litigation, as this is the area of law that places the greatest demands on scientific evidence.I acknowledge at the outset that this is not new ground, but it is ground infrequently traveled by laboratory scientists. The complex and sometimes contentious relationship between science and law is the subject of countless law review articles and amicus briefs, not to mention a comprehensive five-volume treatise by law professors . Promine“The scientific community’s well-established criteria and institutional mechanisms for evaluating the validity of scientific assertions provide courts with clear and understandable guidance on how they can rationally and consistently evaluate scientific evidence. Courts should admit scientific evidence only if it conforms to scientific standards and is derived from methods that are generally accepted by the scientific community as valid and reliable .”Though this counsel serves as an ideal, much of the landscape of the scientific enterprise familiar to most practitioners—a “generative adversarial” process that yields ever-growing knowledge and certainty—is distorted or compromised by the “terminal adversarial” approach to truth employed by our courts. In the following discussions, I introduce a number of issues that arise from this particular use of science. Some of these are shared generally—or at least superficially—with the practice of scientific research, including assessment of the trustworthiness of evidence, the degree to which it reflects the consensus of the day, and the probability that it provides a correct solution to a problem in the real world. Other issues are unique to the legal context, including the procedure by which evidence is communicated to the court, and the exigence and resoluteness of decisions. My goal is to highlight areas at the intersection of science and courtroom law that raise interesting and sometimes unresolved questions—particularly when seen from the perspective of the scientific community—and would benefit from greater interdisciplinary collaboration.Scientific investigation and courtroom litigation have many notable differences in concept, history, and procedure , 5, but Analogously, our justice system is a recipient of evidence from many sources intended to support one or another hypothesis before the court. The diversity of evidence received means that it may, or may not, fall within the common experience of the trier of fact. In some cases, the interpretation of evidence is patently obvious (the weapon was in the suspect’s bag), but in other cases (the shampoo contains a carcinogen), additional technical information is needed to guide the trier of fact . That guIn many instances, the expert is someone who has gained subject-matter expertise through unique first-hand experiences in a particular knowledge domain. Suppose, for example, that the court wishes to determine who is at fault for a ship collision in the harbor. The testimony of a skilled tugboat captain might serve as evidence for this determination, as she is likely to possess accurate information about the probabilities of relevant events. This expert testimony may come in the form of a diagnosis , or it may come as a thesis on navigational principles , whFueled by the expansive growth of science over the past century, scientific investigation and courtroom litigation now commonly converge: Scientific evidence is brought before the court to help resolve questions of fact. Broadly considered, those questions are of four types, which science is generally well equipped to address:1) Who broke the law?This is the forensic question, in which a science-based reconstruction of events is used to determine human responsibility for a criminal act. A valid demonstration that DNA found at a crime scene has a high probability of association with a suspect is a common form of scientific evidence introduced in litigation.2) Who is liable for loss or harm?Determinations of causality and responsibility are the focus of tort law, in which science may be used to argue that an act of negligence or intent by one party, or a product  that one party is responsible for, was the cause of loss or harm to another. A demonstration that chemicals introduced into drinking water cause disease is a form of scientific evidence introduced in civil litigation to prove liability .3) What will happen?potential cause for loss or harm. Here, scientific evidence is introduced to make predictions about the future—to identify causal links and probabilities of things that have not yet happened—and the proposed actions/products enjoined or permitted by a civil court ruling. For example, a home developer that plans to alter the topography of its acreage may be prevented from doing so if the science of hydrology predicts a high probability of water damage to the adjacent property of another party.Proposed actions or products may be seen as legal rights of one party, while another party maintains that those actions/products are a 4) Is it new?This is the question of patent law. Because patented inventions are often based on scientific principles and technologies, scientific evidence introduced in litigation can be essential for resolving disputes over novelty. This use of science is different from the others in that its purpose is to establish what an invention is, rather than what happened, what was the cause, and who is responsible.Scientific evidence in the courtroom faces two significant challenges that are less common in other basic research or applied contexts:1) The courtroom “user” of scientific evidence lacks understanding or experienceUnlike physicians and engineers – users of scientific evidence who are educated in scientific methods and principles – those who make decisions in the courtroom based on scientific evidence commonly lack knowledge in the relevant domains. Judges are generalists and juries are routinely composed of laypeople without scientific training. As for other forms of specialized knowledge, scientific experts may be sought to inform the court. There are, however, unique features of science that place unusual demands on an expert.Science has evolved significantly over the past 200 y, acquiring and refining along the way a treasured set of methods and criteria for controlled investigation of natural phenomena in the search for knowledge. The uniqueness and sophistication of this enterprise, its rigorous requirements for quantification and reproducibility, its intolerance of fraud, and the transparency of the historical record are all characteristics that set scientific research apart from other professions. Scientific evidence is not restricted to the experience of any particular individual; it is drawn from a foundational well of knowledge that is continually deepening and maturing. The scholarly journals of modern science are rich repositories of this knowledge, which has become the basis for decision in many practical ventures, such as medicine and engineering. Because aspects of this science frequently exist outside the realm of experience for courtroom users of the information, the desired role of the expert is to communicate science in plain language to educate the jury. But the scientific expert, unlike the tugboat captain, is not intrinsically the source of that information.2) The question demands immediate resolutionThe truth-seeking strategies of scientific investigation and courtroom litigation are both founded on competition and rigorous debate of alternative theories. In practice, however, these adversarial systems operate by fundamentally different rules. Basic science advances through a generative adversarial system, in which disagreement generates testable hypotheses and new discoveries, which can help discriminate between adversarial positions. The result is a progressive accumulation and refinement of knowledge. Law, by contrast, relies upon a terminal adversarial system. Parties in litigation cannot resolve disagreements about cause and effect through further experimentation, as bench scientists might. The battle must be won through existing facts and argument alone.today’s truth – is called for to answer a question of fact.The problem with the terminal approach is epistemological, at least in part, for it is sometimes difficult to recognize scientific truth. And yet truth – and not just any truth, but we decide to accept… We simply stop when we are satisfied that the piles are firm enough to carry the structure, at least for the time being.”“Every test of a theory, whether resulting in its corroboration or falsification, must stop at some basic statement or other which severity of tests to which a theory has been subjected, and the manner in which it has passed these tests, or failed them” . In practice, corroboration is what yields consensus within the scientific community. The reason that consensus is important can be traced to two fundamental limits of measurement: uncertainty and bias. Leaving aside willful misrepresentation, these are the core reasons why scientific evidence may not be trustworthy. In scientific research, uncertainty and bias are mitigated by empirical validation and reproducibility of results. Validation is the footing for any legitimate application of science because it offers a probabilistic estimate of the accuracy of a measured quantity. To be considered a credible basis for action, however, findings must also be reproducible under different conditions and in the hands of different investigators – yielding a state that Popper termed “intersubjective agreement.” .Scientific evidence presented in litigation may meet Popper’s definition of a basic statement, but the needling question for the gatekeeping judge is always whether the “piles are firm enough to carry the structure.” Ever the pragmatist, Popper concluded that the answer can only be assessed as the “degree of corroboration,” measured not simply by the number of tests but also by “the In the absence of corroboration, a basic statement presented as scientific evidence simply lacks the empirical support needed to justify a decision. This is a sensible threshold in the practice of scientific investigation, where additional experiments can be performed and alternative hypotheses can be developed and tested, but it hobbles the practice of courtroom litigation where claims can only be vetted by today’s science. Instead, to satisfy fairness constraints, it is often argued that courts should adopt a liberal approach to the admissibility of scientific evidence, allowing jury appraisal of unorthodox views with the conviction that truth will emerge through the adversarial process . That coBefore considering those strategies, I first summarize current rules for admissibility of scientific evidence to the courtroom, trace how they originated and evolved, and examine how the professions of science and law can collaboratively ensure that courtroom decisions are based on information that can be trusted. Because these topics are deeply embedded in the Law of Evidence, I begin with a brief review of that doctrine.1.Jurors should be chosen not for their communal familiarity with contested events but, rather, as blank slates who might be persuaded by credible evidence.2.Not all evidence is equally credible, requiring that standards be adopted for use.The jury system that is a central component of common law was initially based on the belief that members of the community could be self-informed about a local contest and thus serve as both experts and decision-makers , 15. AllThis transition initiated the instructional approach to jury decisions, in which subject-matter experts are employed to inform juries of the intricacies, context, and meaning of evidence for which they lack the native wisdom and experience to comprehend.In the early days of this practice, experts were called upon to explain evidence regarding the provenance or authenticity of documents, as, for example, in cases of patrimony or trespass, or to provide medical testimony as to the cause of death . AdmissiBecause the vehicle for conveying expert legal testimony is the human mind, it seemed natural to look there for the answer. The academic discipline of psychology – the science of mind – sprouted in the mid-19th century from roots in physiology, physics, and philosophy. By the turn of the 20th century, experimental psychology seemed on the cusp of revealing the causes of perception, cognition, and behavior . TogetheFrye v. United States  in many state courts as well:In doing so, the appellate court issued a ruling in 1923 – a ruling nearly as notable for its brevity (669 words) as for its impact (it is among the most heavily cited rulings in American case law) – that ultimately established an admissibility test for scientific evidence. Known today as the “the thing from which the deduction is made must be sufficiently established to have gained general acceptance in the particular field in which it belongs.” (emphasis added)“Just when a scientific principle or discovery crosses the line between the experimental and demonstrable stages is difficult to define. Somewhere in this twilight zone the evidential force of the principle must be recognized, and while courts will go a long way in admitting expert testimony deduced from a well-recognized scientific principle or discovery, Sufficient evidence that the lie detector yielded accurate results simply did not exist, meaning that “the thing from which the deduction [James Frye’s innocence] was made” was neither shown to be valid nor “sufficiently established to have gained general acceptance.” The court thus found that Marston’s instrument remained on the darker side of the twilight zone, where “the evidential force of the principle” had not yet been recognized.Frye the beginnings of a legal formalization of common-sense criteria for the value of scientific evidence, which go well beyond the earlier “helpful” and “qualified” standards. Consider, for example, scientific evidence brought to show that fingerprints found at a crime scene were left there by a suspect in custody. This is evidence of some import. But as a practical matter, how might we know that it is a sound basis for choice? There are several standards common to the sciences for assessing evidence, which are born from laboratory tests conducted under ground-truth conditions:1.The evidence is obtained using valid methods and is accurate.2.The evidence is reliable and reproducible by others.3.Frye’s “general acceptance” or consensus standard is based on the premise that a community of people with appropriate expertise could not have come to the same conclusion about the evidence unless the methods were valid and the results accurate, reliable, and reproducible.There is consensus that the evidence is a sound basis for decisions. We see in Frye that point to the unique status of scientific evidence and the role of the expert:1.Frye concept of general acceptance is fundamental, as it aligns with Popper’s “degree of corroboration.” Legal theorist Steven Goldberg cited community and communal beliefs as the first of four “Central Dogmas of Law and Science:” “There is in modern America a scientific community capable of forming a consensus on technical matters” ], which was manufactured by Merrell Dow and widely used for decades to quell nausea and vomiting during first-trimester pregnancy. The plaintiff alleged that Bendectin had caused deformities during gestation. Merrell Dow maintained that there was no scientific evidence of a link between their drug and birth defects, but Daubert recruited an expert in the form of obstetrician William McBride, who was prepared to testify on the teratogenic effects of Bendectin. Noting that McBride’s assertions failed to meet the Frye standard of general acceptance by the scientific community, the District Court for the Southern District of California issued summary judgement in favor of Merrell Dow  tested,•whether it has been subjected to peer review and publication,•its known or potential error rate, and•the existence and maintenance of standards controlling its operation, and•whether it has attracted widespread acceptance within a relevant scientific communityFrye standard, these criteria are intended to be flexibly applied at the discretion of the trial judge.Unlike the uncompromising In response, Daubert went on to argue before the Supreme Court that the common law Daubert strengthened the application of evidence law in several ways that conform to the nature of scientific investigation. Perhaps most importantly, Daubert returned the focus to the body of scientific knowledge the expert’s scientific, technical, or other specialized knowledge will help the trier of fact to understand the evidence or to determine a fact in issue;(b)the testimony is based on sufficient facts or data;(c)the testimony is the product of reliable principles and methods; and(d)the expert has reliably applied the principles and methods to the facts of the case.Rule 702 was revised again in 2022 (to take effect December 2023) through amendments proposed by the Advisory Committee on Evidence Rules and subsequently approved by the US Judicial Conference and the Supreme Court . For theDaubert, as seen in the light of evidence standards routinely employed by the scientific community.•Frye “general acceptance” standard and toward attributes of the expert. This partly reflects the fact that it was designed as a general-purpose rule for experts with specialized knowledge, not simply scientific experts. In doing so, however, the Rule fails to highlight scientific consensus, which is a primary determinant of trustworthiness. While consensus is appropriately recognized by Daubert via the “widespread acceptance” criterion, it should not be discretionary; consensus based on corroborative evidence is how we know things are true.Although Rule 702 promotes a healthy focus on the validity of scientific evidence, it turns the emphasis away from the •Frye, and failing to heed Daubert, is the requirement that the expertise arise from the relevant scientific community (“the particular field in which it belongs”). Although the relevant community is sometimes difficult to resolve from a viewpoint outside of the scientific enterprise, it would help to formally distinguish experts who opine on what a scientific instrument  does vs how well it works.The introduction sets a loosely defined bar for qualifications of the expert. Lost from •702a is the helpfulness criterion. Neither the introduction nor 702a speak to qualifications for the communication/education role of the expert, which is a prerequisite for helpfulness when conveying complex evidence. The focus should be placed on the expert’s ability to clearly communicate the relevant science to a lay audience. While parties may apply their own criteria for communication skills, the effect is sometimes obfuscation , which h•702b and 702c define attributes of the evidence itself that qualify it for admission. The emphasis on “sufficient facts or data” to support all facets of the expert’s testimony (702b) is critical to any rational decision based on scientific knowledge. Marston’s lie detector was excluded simply because there were very few facts or data to support claims of validity. The requirement that evidence be a “product of reliable principles and methods” (702c) is also critical. Evidence presented in support of a hypothesis should be empirically validated to reveal the probability that the hypothesis is true. Reproducibility—demonstration that evidence holds up across studies—is also important to overcome errors and biases that may be unique to a given study, and to gain consensus .•Finally, 702d is a requirement that expert opinions not exceed what is possible to conclude given the knowledge base and methods employed – the premise being that, once admitted, a lay jury may not be able to identify false or exaggerated conclusions drawn from complex evidence. Among the important targets of this provision is a tendency to generalize, without evidence, from scientific conclusions about group effects to conclusions about individual cases .In the following paragraphs, I discuss some of the strengths and weaknesses of the Rule, post Daubert on the structure of Rule 702 cannot be overstated. It also continues to complement and clarify application of the Rule. Many courts today adopt a hybrid approach, in which the sensible standards of Daubert are used to bridge gaps in Rule 702. The problematic status of the “expert” nonetheless remains, with far-reaching implications for justice.The positive impact of I have argued that empirical demonstration of validity and reproducibility, and development of consensus within the relevant community, should be the primary criteria for admissibility of scientific evidence. Rule 702 nonetheless specifies criteria based on an expert’s scientific bona fides and ability to assist the trier of fact. This distinction raises an interesting empirical question: What is more persuasive to the trier of fact, the quality of the science or the attributes of the expert? Recent evidence suggests the latter . One migFrye maintains that conclusions about consensus on a specific principle or discovery must be drawn from “the particular field in which it belongs.” The “widespread acceptance” clause in Daubert similarly states that acceptance must exist “within a relevant scientific community.” While it would be hard to argue against these directives, a persistent sticky point has been: What is the relevant scientific community? , which noted the obvious problem – “experts had become partisan advocates rather than neutral givers of opinion”  – the coOn the surface, this neutral advisory function is antithetical to the adversarial system of law practiced in the United States. But it does seem to work in other common law countries, and the pitfalls of adversarial allegiance undermine the credibility of our existing judicial system. The Federal Rules of Evidence do include a provision for court-appointed experts (Rule 706) , which hDaubert, the Supreme Court noted that petitioners and their amici expressed precisely this concern: “exclusion of ‘invalid’ evidence will sanction a stifling and repressive scientific orthodoxy and will be inimical to the search for truth.” Daubert maintains, furthermore, that “Publication…is not a sine qua non of admissibility; it does not necessarily correlate with reliability.” The scientific community, by contrast, adopts a probabilistic view, arguing that publication through peer review correlates with validity but does not guarantee it  the scientists’ ideal that momentous decisions be based upon the highest standards of evidence, b) the practical reality that those standards are sometimes difficult to meet, or that relevant science does not exist, and c) our unassailable right to fairness. This tension is workable, in principle, through compromise, flexibility, and well-reasoned understanding of criteria for scientific truth, but it forms a leaky structure that is easily exploitable, particularly in our age of misinformation. The solution is to promote awareness and vigilance by all parties and to foster collaboration between gatekeeping judges and scientists. “As the knowledge of science and the procedures of law evolve, the need for this ‘cross-pollination’ becomes ever more necessary” .


Electronic health  literacy may play an important role in individuals’ engagement with online mental health-related information.To examine associations between eHealth literacy and psychological outcomes among Nigerians during the Coronavirus disease-2019 (COVID-19) pandemic.This was a cross-sectional study among Nigerians conducted using the ‘COVID-19’s impAct on feaR and hEalth (CARE) questionnaire. The exposure: eHealth literacy, was assessed using the eHealth literacy scale, and psychological outcomes were assessed using the PHQ-4 scale, which measured anxiety and depression; and the fear scale to measure fear of COVID-19. We fitted logistic regression models to assess the association of eHealth literacy with anxiety, depression, and fear, adjusting for covariates. We included interaction terms to assess for age, gender, and regional differences. We also assessed participants’ endorsement of strategies for future pandemic preparedness.This study involved 590 participants, of which 56% were female, and 38% were 30 years or older. About 83% reported high eHealth literacy, and 55% reported anxiety or depression. High eHealth literacy was associated with a 66% lower likelihood of anxiety  and depression . There were age, gender, and regional differences in the associations between eHealth literacy and psychological outcomes. eHealth-related strategies such as medicine delivery, receiving health information through text messaging, and online courses were highlighted as important for future pandemic preparedness.Considering that mental health and psychological care services are severely lacking in Nigeria, digital health information sources present an opportunity to improve access and delivery of mental health services. The different associations of e-health literacy with psychological well-being between age, gender, and geographic region highlight the urgent need for targeted interventions for vulnerable populations. Policymakers must prioritize digitally backed interventions, such as medicine delivery and health information dissemination through text messaging, to address these disparities and promote equitable mental well-being. Coronavirus Disease 2019 (COVID-19) pandemic has had a considerable impact on physical and psychosocial health , 4. WhilElectronic health  includes health-related services and information delivered or enhanced through the internet or related health technologies , includiCOVID-19 poses critical challenges to the utility of eHealth literacy, for which the World Health Organization and other agencies warned strongly against infodemics; “an overabundance of information and rapid spread of misleading and fabricated news, images, and videos, which, like the virus, is highly contagious, grows exponentially, and undermines public health measures and leads to unnecessary loss of life” . The excHealthy eHealth literacy and internet use may be linked to better psychological wellbeing. Previous reports have shown reports of a negative correlation between eHealth literacy and depression, insomnia, and post-traumatic disorder . ImproviWe hypothesized that there would be no significant association between eHealth literacy and anxiety, depression, and fear of COVID-19, after adjusting for age, gender, education and employment.This cross-sectional study was conducted in Nigeria as part of a larger international cross-sectional study on societal perceptions of COVID-19’s impact and preferences for future preparations. As cross-sectional designs help gain insight into population characteristics and behaviors at a given time , it was The inclusion criteria for the study include Nigerians who could understand English. Although Nigeria has over 250 ethnic groups, with each ethnic group having indigenous languages, English is the national language of communication . SimilarSocial media platforms were the preferred recruitment methods to reach participants across the six geopolitical zones, specifically WhatsApp, Facebook, Twitter, LinkedIn, and Instagram. Participants were recruited from various tertiary institutions and National Youth Service Corp (NYSC) camps across various regions in Nigeria to facilitate representation . Initialp < 0.001)  questionnaire , launche< 0.001) . Partici< 0.001) .post hoc Bonferroni correction was used to adjust for multiple comparisons; Bonferroni thresholds for each subgroup analysis was set by dividing the alpha level (0.05) by the number of pairwise tests. Descriptive statistics were also used for participants’ responses to the most important preparations for future pandemics, displaying this in a Likert chart.Data were analyzed using Stata Statistical package and R Programming. Data were meticulously organized and underwent thorough quality control procedures to ensure its accuracy and integrity, including checks for missing responses, duplicates, and inconsistencies. Missing data was determined to be missing at random (MAR) and were excluded from the final analyses. A sum score of the eHEALS scale was obtained and dichotomized into “low” and “high” using a ≥ 26 cut point . PsycholEthical approval was sought and obtained for the study, which has been reported in the study protocol . The autParticipant characteristics stratified by eHealth literacy level are shown in About 83% of the sample had high eHealth literacy. Higher eHealth literacy was associated with 66% lower odds of both depression  and anxiety , after accounting for age, gender, education, and employment. There were no observed statistical associations between eHealth literacy and fear of COVID-19 .We observed differences in the associations between eHealth literacy and psychological outcomes by age, gender, and geographical region –S6. AfteHigh eHealth literacy was not associated with depression, anxiety, or fear of COVID-19 among persons aged 18–24 years; however, among those aged 25–29 years, there was 82%  and 76%  lower likelihood of depression and anxiety, respectively. Among persons older than 30 years, the odds of anxiety were 62%  lower for those with high eHealth literacy compared to those with low eHealth literacy . The BonAmong participants living in the Northcentral region of the country, high eHealth literacy was associated with 22%  lower odds of depression and 28%  lower odds of fear of COVID-19. For those living in the Northwest, high eHealth literacy was linked to 43%  and 40%  lower odds of depression and anxiety, respectively. Persons living in the South region with high eHealth literacy were 33%  and 32%  less likely to report depression and anxiety respectively; while the odds of depression  and anxiety  was 10% lower for persons living in the Southwest with high eHealth literacy . There wMany of the strategies were rated important . The panWe examined the association between eHealth literacy and psychological outcomes during the COVID-19 pandemic in Nigeria. Our study showed five key findings; first, majority of our participants have high eHealth literacy levels. Second, the prevalence of self-reported anxiety and depression is also substantial. Third, high eHealth literacy was associated with a lower likelihood of anxiety and depression, and fourth, there are age, gender, and geographical differences in the association between eHealth literacy and psychological outcomes. Finally, eHealth-related strategies such as medicine delivery, receiving health information through text messaging, and online courses were highlighted as important strategies for future pandemic preparedness . These fOur findings on high eHealth literacy can be explained by the increased mobile phone usage in Nigeria reported during the pandemic , 35. ThiThe prevalence of self-reported anxiety and depression in this study aligns with previous studies that reported a range of psychological issues among Nigerians during the pandemic . This inWe found an association between higher eHealth literacy and lower odds of both depression and anxiety. Previous studies reported an inverse correlation between eHealth literacy and depression and that improving eHealth literacy may contribute to maintaining good psychological well-being , 22. MenThere were age, gender and geographical differences in the association between eHealth literacy. Among women with high eHealth literacy, the likelihood of anxiety and depression was lower compared to men. This corroborated with other studies that have shown that being female, less than 75 years old and having a higher education are associated with eHealth literacy . ReasonsResults from future pandemic strategies endorsed by participants further support the need for health technology-backed interventions in Nigeria. Medicine delivery, receiving health information through text messaging, online courses, food delivery, and receiving health information through social media were endorsed as strategies important to prepare for future pandemics and crises. These are mostly digital interventions that may significantly contribute to improving the health of Nigerians; partnerships between context experts like healthcare workers and digital content experts may further advance such interventions . It is iOur study should be interpreted in the context of these limitations. First, this was a cross-sectional design; hence, there was no temporality. Second, the survey was originally designed in Hong Kong and may not have initially included Nigeria in the original context; however, modifications were made to adapt certain survey items to the Nigerian context. Third, our study’s participants were mostly young adults from the Southwestern region, which may have contributed to the high level of eHealth literacy observed; hence, findings from this study might not be generalizable to Nigerians with low literacy, non-social media users and older adults. Fourth, the survey was administered digitally and may have excluded persons with limited digital literacy. Nevertheless, this study has some strengths. First, to our knowledge, this is one of the first studies to examine the associations between eHealth literacy and anxiety and depression in a Nigerian sample. In addition, we employed various recruitment strategies to ensure that participants from different regions of the country were represented in the sample.Our findings have important implications for the development of interventions to address the scarcity of mental health services in Nigeria. The high eHealth literacy in Nigeria and high use of smartphones and mobile application makes the Nigerian environment suitable for digital health interventions. Participants-endorsed strategies for preparation for future pandemics are critical policy options that may inform healthcare policies. Strategies such as receiving credible health information through social media platforms. Future intervention strategies could leverage digital tools and platforms to provide remote mental health services and incorporate other chronic conditions. Given the critically low performance and ranking of the Nigeria health system , 48, theIn conclusion, our study showed high eHealth literacy among our sample of Nigerian adults. Self-reported prevalence of anxiety and depression is also considerably high in the face of prevalent economic and structural hardship and limited access to mental health services. High eHealth literacy was associated with psychological outcomes of anxiety and depression. eHealth literacy-informed interventions can be invested in to address several pressing health issues in Nigeria and prepare for future pandemics and health-related crises. The age, gender and regional differences observed present important intervention opportunities for interventions. Additionally, digital solutions focused on medicine delivery, receiving health information through text messaging, online courses, etc., are important health technology-backed intervention opportunities in Nigeria. The Nigerian environment may be suitable for digital health interventions to increase access to mental healthcare services due to the country’s high smartphone usage and eHealth literacy, as shown in this study’s result. Importantly, there is a need for health policies that promote the implementation of telemedicine and digital health interventions in Nigeria and guarantee equitable funding of health systems in the various regions of the country in order to enhance access to health services.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 20-272). The patients/participants provided their written informed consent to participate in this study.EC, MH, KL, JW, and DF conceived the idea for the study and designed the study. OA, OAF, IF, JL, and OO contributed to recruitment and data collection. JL contributed to data collection and management. OO performed data analyses and visualizations for the country-specific data. OA, KA, OAF, and OO wrote the original draft. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Trustworthy clinical practice guidelines represent a fundamental tool to summarize relevant evidence regarding a set of clinical choices and provide guidance for making optimal clinical decisions. Clinicians must differentiate between guidelines that provide trustworthy evidence guidance and those that do not. We present six questions clinicians should ask when evaluating a guideline’s trustworthiness. (1) Are the recommendations clear?; (2) Have the panelists considered all alternatives?; (3) Have the panelists considered all patient-important outcomes?; (4) Is the recommendation based on an up-to-date systematic review?; (5) Is the strength of the recommendation compatible with the certainty of the evidence?; (6) Might conflicts of interest influence the recommendations? If yes, were they managed? Once the conclude they are dealing with a trustworthy guideline, clinicians must gain an understanding of the transparent evidence summary that the guideline will offer, and judge the applicability of trustworthy recommendations to their patients and settings. Consideration of the circumstances and values and preferences of patients will be crucial for all weak or conditional recommendations. The practice of evidence-based medicine presents challenges. Clinicians typically may not have the skills or the time to review primary studies, or even systematic reviews, to determine their rigor and carefully consider their results and implications for practice , 2.To address this issue, trustworthy clinical practice guidelines should serve as a fundamental tool to summarize the evidence and provide guidance for clinical decision-making. Guidelines may, however, be well or poorly conducted and, if poorly conducted, offer guidance that is not in patients’ best interests. Thus, it is incumbent on clinicians to differentiate between guidelines that are trustworthy from those that are not.. Given the limitations of existing guidelines, users require an approach to recognize trustworthy practice guidelines.Guidelines remain inconsistent in their development, reporting, and management of conflicts. Indeed evaluations of guideline rigor using existing checklists   recommenHave the panelists considered all patient-important outcomes?While clinical trials often focus on primary outcomes, patients choosing between alternatives are typically interested in a number of consequences that will ensue depending on their choice. These may include mortality and major morbid events such as stroke, and outcomes related to quality of life, such as function and pain, typically measured using patient-reported outcome measures. Trustworthy guidelines must consider all patient-important outcomes, including both benefits and harms.What guidelines should not focus on is outcomes, such as hypoxemia, a physiology score, or cardiac output, that may be biologically compelling but are not in themselves important to patients. We call such outcomes “surrogate” or “substitute” endpoints that act as stand-ins for what is important to patients. To distinguish between a surrogate and a patient-important outcome one can ask oneself the following question: if the outcome under consideration were the only one to improve with treatment, would the patient be interested in using a treatment associated with harms and burdens? Patients told that a treatment that improves their oxygenation, their physiology score, or increases cardiac output but does not prolong their lives, prevent major morbid events, make them feel better, or shorten their stay in a critical care unit would not be interested. Oxygenation, physiology score, or cardiac output are therefore surrogate outcomes. In contrast, patient-reported outcomes such as breathlessness or quality of life are important to patients and their treating physicians, are often the reason for their presentation and often do show low correlations with surrogates.Why would guideline developers be tempted to rely on such surrogates? Clinical trialists often focus on surrogate laboratory markers and imaging results because they can conduct much shorter trials with many fewer patients than would be required to detect effects on mortal or major morbid outcomes. Indeed, surrogates may be all that existing trials have addressed.In such instances, guidelines should specify the patient-important outcome for which the surrogate outcome is standing in and acknowledge that indirect evidence leaves uncertain the impact of the intervention on the corresponding patient-important outcome. A treatment that increases cardiac output may or may not improve function and reduce hospitalizations, and one that improves oxygenation may or may not reduce mortality in patients with acute respiratory distress syndrome (ARDS).Guidelines must consider both benefits and harms. The importance of harms is likely relative to the harm presented by the clinical condition and thereby the potential for benefit for mitigating harm. While in life-threatening circumstances, such as necrotizing fasciitis, patients tend to accept higher risks of treatments such as emergency fasciotomy, risk tolerance will be lower in chronic diseases in which benefit is likely to be more modest.The Intensive Care Society has issued recommendations suggesting the use of subglottic secretion drainage to reduce ventilator-associated pneumonia (VAP), duration of mechanical ventilation, and length of the ICU stay. In making their recommendation, they make no reference to complications related to the procedure  that incIs the recommendation based on an up-to-date systematic review?New evidence may differ from prior study results; thus, recommendations may also change. Recombinant activated protein C in septic shock provides an example of such an evidence shift. Activated protein C, once promoted for septic shock , ultimatFor example, the 2021 European Society of Cardiology (ESC) Guidelines  for the Is the strength of the recommendation compatible with the certainty of the evidence?Recommendations may be strong  versus weak or conditional . The GRADE approach , endorseIn the GRADE formulation, a panel issues strong recommendations when benefits clearly outweigh downsides — or the reverse. When the balance is less certain, panels issue weak recommendations. When clinicians see a strong recommendation, they can infer that all or almost all fully informed individuals would choose the same treatment option; when they see a weak or conditional recommendation they can infer that the majority of informed patients would choose the recommended option, but a minority, typically because of different values and preferences, would not.In general, guideline panels should not issue strong recommendations in the face of low certainty evidence: if one is uncertain of the benefits, harms, and burdens of a treatment, it is very unlikely that one will be confident that the benefits outweigh the downsides, or the reverse. There are, however, exceptional circumstances when a panel may reasonably make a strong recommendation in the face of low certainty evidence. These include (1) life-threatening conditions, (2) uncertain benefit with certain harm, (3) options equivalent in benefits with one being less harmful or costly, and (4) potential catastrophic harm . GeneralDetecting such a problem — indeed, making any judgment of whether the evidence warrants the panel’s recommendation — requires a transparent and easily understandable presentation of the evidence, including absolute estimates of benefits and harms of the interventions. GRADE suggests including summary-of-findings (SoF) tables –28 to acIn Fig. Clinicians can rely on strong recommendations in trustworthy guidelines while weak recommendations require shared decision-making with patients and/or their representatives. Such conversations involve understanding the values and preferences of patients — either directly or through insights from their representatives — and coming to a decision consistent with those values and preferences . While oAn example of where further transparency would be desirable is in the 2020 “International evidence-based guidelines on Point of Care Ultrasound (POCUS) for critically ill neonates and children” by the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) . AlthougMight conflicts of interest influence the recommendations? If yes, were they managed?“A conflict of interest exists when a past, current, or expected interest creates a significant risk of inappropriately influencing an individual’s judgment, decision, or action when carrying out a specific duty” . ConflicReaders of guidelines may overlook the importance of financial, professional, and intellectual COI: indeed, judging whether COI influence the trustworthiness of a guideline can be challenging. Nevertheless, this assessment plays a key role in determining the credibility of a guideline.p = 0.1) with the presence of radiologists on the guideline, and was associated with the number of recent breast cancer publications by the lead author (p = 0.02) [Although we and other critics of guidelines frequently highlight the need to consider conflicts, the extent to which they actually influence recommendations remains uncertain: A 2020 systematic review of studies evaluating the relative risk of conflicts of interest being associated with favorable recommendations in guidelines was 1.26  , a confi = 0.02) .After addressing the six questions and determining that a guideline is trustworthy, clinicians still need to assess whether the recommendations are applicable to their clinical practice. Recommendations from a guideline will be specific to a population and setting. Clinicians should assess the extent to which their patients and setting match those of the recommendations.The Australian and New Zealand Living Clinical Guidelines for Stroke  made a sIn the same guideline, the panel strongly recommends that “all stroke patients should be admitted to hospital and be treated in a stroke unit with an interdisciplinary team” . This reIn summary, clinicians must evaluate the trustworthiness of a guideline, understand the transparent evidence summary that trustworthy guidelines will offer, and judge the applicability of trustworthy recommendations to their patients and settings. Consideration of the circumstances and values and preferences of patients will be crucial for all weak or conditional recommendations.In considering whether to attend to a particular guideline, clinicians should ask themselves six questions — clarity of the recommendation; consideration of all available therapeutic, diagnostic, or prognostic options; consideration of all patient-important outcomes; recommendation should be based on an up-to-date systematic review; strength of the recommendation should be compatible with the certainty of the evidence; and conflicts of interest. Finally, if a guideline is judged credible, clinicians must then assess whether it is applicable to a patient and clinical setting.


BA) in the DAT, the GABA transporter 1 (GAT1), and the glycine transporter 1 (GlyT1b); this current is proportional to the current generated by the substrate, respective to the transporter. Interestingly, a second consecutive OCA application to the transporter fails to elicit a response. The full displacement of BAs from the transporter occurs only after exposure to a saturating concentration of a substrate. In DAT, perfusion of secondary substrates norepinephrine (NE) and serotonin (5-HT) results in a second OCA current, decreased in amplitude and proportional to their affinity. Moreover, co-application of 5-HT or NE with OCA in DAT, and GABA with OCA in GAT1, did not alter the apparent affinity or the Imax, similar to what was previously reported in DAT in the presence of DA and OCA. The findings support the previous molecular model that suggested the ability of BAs to lock the transporter in an occluded conformation. The physiological significance is that it could possibly avoid the accumulation of small depolarizations in the cells expressing the neurotransmitter transporter. This achieves better transport efficiency in the presence of a saturating concentration of the neurotransmitter and enhances the action of the neurotransmitter on their receptors when they are present at reduced concentrations due to decreased availability of transporters.Synthesized in the liver from cholesterol, the bile acids (BAs) primary role is emulsifying fats to facilitate their absorption. BAs can cross the blood-brain barrier (BBB) and be synthesized in the brain. Recent evidence suggests a role for BAs in the gut-brain signaling by modulating the activity of various neuronal receptors and transporters, including the dopamine transporter (DAT). In this study, we investigated the effects of BAs and their relationship with substrates in three transporters of the solute carrier 6 family. The exposure to obeticholic acid (OCA), a semi-synthetic BA, elicits an inward current (I Bile acids (BAs) are a large family of molecules which act as a detergent supporting absorption and digestion of lipids. They are derived from cholesterol, synthesized in the liver, and accumulated in the gallbladder. In response to food intake, BAs are released into the duodenum . The entUnder physiological conditions, 20 different kinds of BAs can be detected in rodents and human brains . Both coIt is well-established that BAs influence complex physiological behaviors through their targets in the brain. Both the Takeda G protein-coupled receptor 5   and the There is also the possibility of a physiological role for BAs in the modulation of brain activity through pathways other than their physiological targets. Direct activation of multiple targets important in neuromodulation has been described, such as muscarinic receptors , NMDA S and GABAXenopus laevis oocytes and two-electrode voltage clamp experiments investigating the currents under different conditions. Using molecular docking simulations, we also identified putative OCA binding sites, which could alter the transport cycle stabilizing DAT in an occluded conformation.Recently, we have shown that OCA  and the dopamine transporter DAT (SLC6A3) interact directly . This waXenopus laevis oocytes. In this work, we investigated the interaction of BAs with DAT, and assessed if those interactions are shared with other SLC6 family members, namely GAT1 and GlyT1b.Dopamine transporter is a neurotransmitter sodium symporter (NSS) belonging to the solute carrier 6 (SLC6) family. The SLC6 transporter family is essential in the homeostasis of neurotransmitters, nutrient molecules and, osmolytes; it has a fundamental role in controlling membrane potential  in both 2 1.8, MgCl2 1, HEPES 5, pH7.6; NDE: ND96 plus 2.5 mM pyruvate, 50 μg/ml gentamycin sulfate, penicillin streptomycin solution, 10 U/ml. The external control solution for electrophysiological studies (ND98) had the following compositions (in mM): NaCl 98, MgCl2 1, CaCl2 1.8 and HEPES 5. The final pH was adjusted to 7.6 with NaOH. Substrates used were dopamine (DA) , γ-Aminobutyric acid (GABA) , SKF89976A , glycine , 5-hydroxytryptamine (5-HT) , lithocholic acid (LCA) , and obeticholic acid (OCA) . LCA and OCA powder were dissolved in DMSO at 50 and 100 mM, respectively.The ND96 and NDE solutions used during oocyte preparation and culture had the following compositions (in mM): ND96: NaCl 96, KCl 2, CaClXenopus laevis females. Animals were anesthetized in 0.1% (w/v) MS222  solution in water. Abdomens were sterilized with the antiseptic agent (Povidone-iodine 0.8%), laparotomy was performed, and portions of the ovary were collected. The oocytes were treated with 1.5 mg/ml collagenase  in ND96 calcium-free for at least an hour at 18°C. Healthy and fully grown oocytes were selected and stored at 18°C in NDE solution . For specifications about the constructs, see The oocytes were obtained from adult solution . The expElectrophysiological studies were performed using the two-electrode voltage clamp (TEVC) technique . The controlling software was WinWCP version 4.4.6  or Clampex . Borosilicate microelectrodes, with a tip resistance of 0.5–4 MΩ, were filled with 3 M KCl. Bath electrodes were connected to the experimental oocyte chamber via agar bridges (3% agar in 3 M KCl). The holding potential was kept at −60 mV for all the experiments. Data analysis was performed using Clampfit 10.2 software ; OriginPro 8.0  and GraphPad Prism 8.0.2  were used for statistical analysis and figure preparation. The values reported are the mean ± SE; statistical analysis was done with ANOVA one-way and repeated measures ANOVA.0OCA or I0LCA as the transient current elicited due to the first (0) exposure of OCA or LCA, respectively. I’OCA refers to the transient current elicited by any other exposure to OCA followed by the first one. IS (S is substrate) represents the current elicited by the transport of the indicated substrate.We have defined IX. laevis oocyte heterologously expressing mDAT, generated an inward transport current (IDA) of about 25 nA, and OCA 10 μM elicited an inward transient current (I0OCA) of about 60% of IDA; a second applications of OCA (I’OCA) did not elicit a similar response (0OCA and I’OCA (nearly undetectable) measured on the same oocytes are statistically different (p < 0.0001). Their relationship is independent of the washing time (from 1 to 15 min) or the concentration of the second dose (data not shown). Furthermore, repeated applications of another BA with lower affinity , over a response . The amp0OCA. After the first exposure to OCA, cells were washed with ND98, followed by DA 30 μM perfusion. The second exposure to the OCA elicited a current I’OCA with an amplitude identical to I0OCA  (p < 0.0001).To investigate the dependency of the amplitude of the I’for mDAT , after tOCA identical in amplitude (p > 0.9999) and shape to I0OCA  defines the potency of different agonists and antagonists of monoamine transporter  to inhibit the DA radiolabeled uptake  for NE was −12.49 ± 0.79 nA, and for 5-HT −11.76 ± 1.28 nA, i.e., 53% and 45% of the Imax for DA, respectively. The apparent substrate affinity K0.5 for NE was 10.76 ± 1.67 μM, and for 5-HT 36.98 ± 10.77 μM (max and K0.5 (Imax/K0.5), of DA, NE, and 5-HT in mDAT  and I0OCA (OCA 10 μM), NE was perfused, which resulted in INE of about 57% of IDA (as shown above). Interestingly, the following exposure of oocytes to OCA 10 μM elicited an inward transient current I’OCA, which was significantly (p = 0.001) reduced in amplitude compared to I0OCA (about 56% of I0OCA)  than I0OCA (p < 0.0001)  and giving rise to the maximal OCA current.Since DAT can translocate NE and 5-HT, even with reduced efficiency and lower affinity as reported above, we repeated the experiments of f I0OCA) . Applyin 0.0001) . FinallyTo verify if the interaction of BAs is specific and limited to DAT or extended to other SLC6 transporters, we selected two other members of the family: GAT1 and GlyT1b. The experimental protocol reported in GABA (−217.8 ± 14.57 nA). The subsequent perfusion of OCA (10 μM) generated a proportionally large transient inward I0OCA (−123.6 ± 8.32 nA) (The perfusion of GABA 300 μM on oocytes expressing rGAT1 elicited a large and inward transport current I8.32 nA) .Gly (−88.24 ± 11.15 nA) and OCA 10 μM gave rise to a transient inward I0OCA (−51.88 ± 6.70 nA)  .LCA  was about 60% of the substrate currents (IS), as shown in p > 0.99), indicating that OCA has comparable effects in all transporters tested, effects that are proportional to their specific transport-associated current amplitude.All three transporters investigated here  have shown different amplitudes of substrate transport currents . In the presence of OCA (or LCA), the amplitude of the IOCA, expecting that in GAT1 the second exposure of OCA might result in a detectable current. The I’OCA indeed generated a current; however, significantly reduced to 6% of I0OCA   .GABA with an amplitude comparable to the first one (p = 0.1599), and the re-exposure to OCA 10 μM induced an inward transient current of I0OCA (p > 0.99)  , consist > 0.99) .0.5 at −60 mV (OCA was reduced to the 53% of the I0OCA (p < 0.0001) . Furthermore, the application of OCA did not alter the amplitude of IGABA (OCA (10% of the I0OCA) (p = 0.0019). This reduction was consistent with the decrease of the GABA transport current (p = 0.0003)  . Exposinof IGABA . SKF8997of IGABA . After G 0.0003) . The facThis data reported in Xenopus laevis oocytes expressing mDAT, OCA and LCA elicited a sodium transient inward current  in DAT; a regular transient inward current is visible only when preceded by the perfusion of DA. When the oocytes are perfused with a concentration of DA lower than the saturating one, I’OCA is significantly smaller than I0OCA. These observations suggest that the OCA molecules bound to DAT are not displaced from the transporter by simple buffer washing, and that only the presence of saturating concentrations of DA completely remove OCA from its binding site. This results in a second OCA current with reduced amplitude . We thus hypothesize that I’OCA amplitude is directly correlated to the unbinding of the OCA from the transporter. To test this hypothesis, we exposed the oocytes to lower affinity substrates of DAT, like NE and 5-HT. As our data show  and GlyT1b (neurotransmitter member of the amino acid transporters). In oocytes expressing rGlyT1b or rGAT1, the perfusion of BAs produces a current that is larger than that recorded in mDAT, and proportional to the current induced by the specific substrate. The fact that the OCA current was proportional to the transport current supports the idea that this conductance triggered by OCA should be mediated by the rearrangement of the transporter , 5.This binding is not exclusive to OCA perfusion, as GlyT1b and GAT1 respond to the application of LCA as well. LCA is a natural bile acid that shares with OCA the same sterol-based structure, with the ethyl and hydroxyl groups present in OCA substituted by hydrogen in LCA. This observation is important not only to assess that a similar interaction with transporters occurs even in the presence of different residues, sharing common binding mechanisms, but also concerning the pathophysiological role of endogenous BAs, which, for example, increase in the systemic circulation after bariatric surgery and may act on different targets in the central nervous and enteric systems .OCA current reduced in amplitude, confirming what was previously seen in DAT.We further investigated these interactions, using the same approach of multiple OCA applications, to characterize the removal of OCA bound to these transporters. In GlyT1b and GAT1, the second exposure to BAs does not elicit reliable responses, suggesting that as in DAT, the first BA bound to the transporter makes its binding site inaccessible to other BAs molecules. BAs do not modify GAT1 kinetic transport parameters, confirming that these molecules act only on the transporters in the absence of substrate. Perfusion of GABA at a concentration lower than saturating, after the first OCA application, caused an I’In conclusion, BAs act on the tested members of the SLC6 family members similarly: upon binding, they induce a conformation rearrangement that opens a transient conductance and while bound, the BAs prevent the action of another BA molecule. This occluded conformation can be recovered only in the presence of substrates . ConsequThe characterization of the action of BAs on three members of SLC6 is a first step in investigating the relationship between the SLC protein and BAs, a class of molecules that are also present in the brain. Identifying the structural determinants of these transporters involved in BAs binding might provide fundamental information in drug discovery to identify new therapeutic uses for BAs, considering that studies focused on the use of BAs as a treatment for brain conditions are rapidly growing  and thatThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This animal study was reviewed and approved by the Committee of the “Organismo Preposto al Benessere degli Animali” of the University of Insubria and nationally by Ministero della Salute (permit nr. 449/2021-PR).TR, MB, and AD performed the experiments. TR analyzed the data and prepared the figures. TR and EB wrote the manuscript. DZ and MB contributed to editing the manuscript. AG, DZ, and EB designed and supervised the studies. All authors contributed to the article and approved the submitted version.


Updating evidence-based clinical practice guidelines is an onerous process and there is a call for more efficient determination of key questions that need updating. Especially for surgical techniques it is unclear if new evidence will result in substantial changes after wide implementation and if continuous updating is always necessary.This study analyses the impact of updating a surgical guideline and proposes suggestions for optimising this process.The Dutch Minimally Invasive Surgery guideline was developed in 2011 and updated in 2021. For both versions a multidisciplinary guideline working group (GDG) was created, that determined key questions. Changes in conclusions and recommendations were analysed by the GDG and statements for expected change of recommendations in the future were made.15 key questions were formed, of which 12 were updates of the previous guideline. For only 27% of the updated key questions, the conclusions changed. In ten years, the body grew only marginally for most key questions and quality of the evidence did not improve substantially for almost all key questions. However, in this first update of the MIC guideline, many recommendations did change due to a more robust interpretation of the conclusions by the GDG. Based on analysis of this updating process, the GDG expects that only four out of 15 recommendations may change in the future.We propose an additional step at the end of guideline development and updating, where the necessity for updating in the future is determined for each key question by the GDG, using their valuable knowledge gained from developing or updating the guideline. For surgical guidelines, the authors suggest updating key issues if it includes a relatively newly introduced surgical- or adapted technique or a new patient group. Low quality or small body of evidence should not be a reason in itself for updating, as this mostly does not lead to new evidence-based conclusions. This new step is expected to result in a more efficient prioritising of key questions that need updating.By adding one additional step at the end of the updating process, the future updating process could become more efficient. Evidence-based clinical practice guidelines (CPG) include recommendations intended to optimise patient care. These recommendations are based on a systematic review of evidence and help to translate evidence into clinical practice . The groDue to systemic reviewing of the extensive available literature, guideline development is a demanding and time-consuming process, while it should be both efficient and cost effective . BecauseIn particular, guidelines on new  techniques and technologies are labelled with the need to be updated after implementation as it is expected that new data will become available regarding their clinical impact. However, for these guidelines, it is unlikely evidence will change substantially once techniques are widely implemented .The aim of our study is to pose suggestions for optimising the efficiency of this process based on experiences of a multidisciplinary surgical guideline updating process.For this manuscript, we used the Dutch Minimally Invasive Surgery (MIS) guideline to analyse the updating process. This guideline was first developed in 2011  and updaFor both versions, a multidisciplinary guideline development group (GDG) was created to respectively develop and revise the guideline. One gynaecologist (FWJ) was member of both GDGs.Both guidelines were developed with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument . The GDGFor the 2011 guideline, the methodological quality of the studies was assessed using the Grading System from the Dutch Institute for Healthcare Improvement (CBO), which consisted of levels A-D for study quality and conclusion quality level A-D. For the 2021 guideline, the Grading Recommendations Assessment, Development and Evaluation (GRADE) system was used. GRADE distinguishes four grades for the quality of scientific evidence: high, moderate, low, and very low. .The key questions were analysed for both versions of the guideline. Evidence level, recommendations, and changes in recommendations were noted. Additionally, after finishing the guideline, the 2021 GDG members, also being the authors of this manuscript, considered all changes in evidence and recommendations and prepared a statement for each recommendation if it is expected that future updating would result in new recommendations, which resulted in this manuscript.Table II shows the changes in recommendations compared to the previous guideline, including the quality of evidence and the reason for the change. The 13 key questions resulted in 15 recommendations, based on 15 evidence-based conclusions. 12 recommendations were updates from the previous guideline, and 3 recommendations were new.For 2 key questions, the conclusions did not change, and the recommendations also stayed the same. For 6 questions, the evidence- based conclusions did not change, but the recommendations were changed. This was mostly because of more robust interpretation of the evidence by the GDG or more widely experience with the technique. In the 2011 guideline, little evidence was available, and the techniques were relatively new. Therefore, many recommendations were authority based to give the much-needed guidance at that moment. However, with now more experience with all techniques, the GDG changed the recommendations in accordance with the evidence-based conclusions. For 3 questions the conclusions did not change, however due to a larger body of evidence, the recommendation changed. For 2 questions the conclusions changed and therefore the recommendations.Even with a growing body of evidence, almost all evidence was graded very low GRADE, despite only including randomized controlled trials (RCT) and systematic reviews (SR). The evidence was mostly downgraded due to imprecision and risk of bias.For 11 recommendations, the GDG expects that the future updating would not result in a change of the recommendation or that this topic is not a key clinical issue anymore in the future. This is suggested as the techniques are widely used and all considered safe, or because no new evidence is expected in the future as this has not appeared in the last 10 years. For four recommendations the GDG expects or believes it possible that new evidence will be available which may change recommendations. For example, because the described patient group is growing or because it describes a new technique.Our results show that after 10 years, most evidence- based conclusions have not changed. For most key questions, the body of evidence either stayed the same or grew without changing the conclusions. However, for some, the body grew and resulted in clinically relevant different conclusions. The quality of evidence was still low or very low for most issues, despite exclusively including RCTs and SRs and some growth in the body of evidence. For some questions, the evidence-based conclusions mostly did not change, but recommendations did. This was largely due to the more robust interpretation by the GDG and wider implementation of the technique for special patient groups and alternative techniques.The efficiency of a surgical guideline updating process is cumbersome. In future updating, we should ask ourselves if this could be performed more efficiently and what could aid to this goal.Albeit it is important that guidelines reflect the currently available evidence; estimating when and if an update of recommendations will result in changes is difficult.Vernooij et al.  already As many authors recognise the limited resources available for updating processes, the need for an optimal selection process for partial updating is high . AgbassiThe above-mentioned highlights that it can be difficult for the new GDG to determine which key issues do not need updating. In our opinion, the current GDG could be of added value in this prioritising step. This GDG has mastered the available evidence and has insight in the need and value of new evidence that can change the conclusions. Additionally, many prioritising systems suggest the first steps of prioritising performed by epidemiologists. Although we encourage epidemiologic support during updating processes, we do believe that clinicians should be leading prioritising. As the time span between development and updating or between updating processes is long, the new GDG composition has often changed, inherently the valuable knowledge of the old GDG group is lost.Key issues are often considered relevant for updating if the previous conclusions were based on low quality or a low body of evidence. Studies have shown that low-quality evidence in CPGs is a frequent problem in various fields of medicine, including surgical ones . HoweverTo optimise efficiency of selection of key issues for updating, we propose a new crucial step in surgical guideline development and updating. At the end of the process, after formulating the recommendations, the GDG states if it is likely that recommendations will change in the future, including the expectation if an issue will still be a key issue in the future. This statement is based on the already available evidence, the changes in evidence in the last years, and implementation of the techniques. We have implemented this suggestion for the updated guideline . Our resFor our updated MIS guideline, this first extended updating process was valuable. Although only a small amount of evidence-based conclusions changed, multiple recommendations changed. During the development of the first MIS guideline, there was a high need for clinical guidance using these new techniques. Although evidence-based conclusions showed no superiority of a specific technique, the GDG offered authority-based guidance in the recommendation as the conclusions was based on limited evidence and experience with the techniques varied. However, although many conclusions did not change substantially in the updated guideline, the GDG now felt reassured to make recommendations according to the conclusions, as the experience with all techniques has grown substantially and sometimes the body of evidence also grew. These experiences strengthen our recommendation to suggest at least one future update for recommendations regarding new techniques. However, after wide implementation and the conclusion that little new evidence has come available, there is not always the need to keep updating all questions. In case of our MIS guideline, only a small number of questions need updating in a future update and resources could be spent on other clinical questions.Although we describe experiences from a surgical guideline process, we do believe our suggestions are generalisable to other medical fields. The need for prioritisation is not limited to surgical guidelines, and developed prioritizing steps also are suggested to implement widely . TherefoIn a world with limitless resources, full updating processes are justifiable, however, this is not contemporary reality. In the present time we need to be more efficient with resources and we should focus on efficient ways to perform the best evidence- based care possible. Our proposed step could aid in this need. Surely, the added value of our suggested step may vary per guideline. For all guidelines, our proposed step, costing little effort, is expected to result in a more efficient key issue analysis with the chance of a more selective group of questions with the need for an update.Updating a guideline is a resourceful process and more efficiency is needed. It is difficult to determine which key issues are relevant to update for a new GDG at the beginning of the process. We propose an additional step by the GDG at the end of the development and updating process of a guideline, where statements are made regarding the expectations that future updating would result in changes of recommendations. The necessity for future updating is determined for all single key questions. In our opinion, one should update key questions if it is a relatively new technique, a new patient group or if a new technique or innovation was added to the surgical palette. However, low quality or a small body of evidence should not be a reason in itself for updating a guideline, as this does not necessarily lead to new evidence-based conclusions.


In this abstract, we review current approaches to the management of uncomplicated urinary tract infection (UTI) and begin to explore alternative approaches to antibiotic prescribing. We review clinical guidelines on the use of nitrofurantoin internationally to capture the level of variation in evidence-based guidance. We find that the evidence base has been interpreted in very different ways. UK guidelines from NICE and the Scottish Intercollegiate Guidelines Network (SIGN) are unusual in promoting short (3 day) courses of nitrofurantoin. We find little direct evidence to support this, and that this guidance has been extrapolated from studies based on other agents. ‘Short’ courses of antibiotics aim to provide optimum balance between providing effective treatment whilst reducing selective pressure driving resistance amongst colonizing microbial flora. Three days of nitrofurantoin may indeed be a useful intervention in a large group of patients. Longer courses of nitrofurantoin still demonstrate considerable rates of treatment failure. The concept of a course length in itself is limited. The variation between recommendations internationally reflects both the uncertain foundations upon which evidence-based guidelines are written, and the limits of what can be safely concluded from evidence. We join others in pointing out there may be ways of customizing duration of therapy to the patient’s response in primary care settings. There is a need for a more patient-focused approach to uncomplicated UTI, including better safety-netting and (currently lacking) guidance on best practice in the common clinical scenario of treatment failure.