Evidence-based medicine (EBM) is generally accepted as the gold standard for high-quality medicine and, thus, for managing patients with tinnitus. EBM integrates the best available scientific information with clinical experience and patient values to guide decision-making about clinical management. To help health care providers and clinicians, the available evidence is commonly translated into medical or clinical guidelines based on a consensus. These involve a systematic review of the literature and meta-analytic aggregation of research findings followed by the formulation of clinical recommendations. However, this approach also has limitations, which include a lack of consideration of individual patient characteristics, the susceptibility of guideline recommendations to material and immaterial conflicts of interest of guideline authors and long latencies till new knowledge is implemented in guidelines. A further important aspect in interpreting the existing literature is that the absence of evidence is not evidence of absence. These circumstances could result in the decoupling of recommendations and their supporting evidence, which becomes evident when guidelines from different countries differ in their recommendations. This opinion paper will discuss how these weaknesses can be addressed in tinnitus. The treatment pathways of tinnitus patients vary largely from country to country and within countries. A tinnitus patient will be offered very different treatments depending on the institutions where the patient presents ,2. This Ebers papyrus, dating back to 1550 BC, already had guidelines on treating tinnitus (strange ear) [To make it easier for clinicians and health care providers to apply the ever-growing body of available evidence judiciously, the evidence is commonly translated into medical or clinical guidelines by a guideline committee . It diffnge ear) . The traIn the field of tinnitus, many different treatments have been offered to patients, which also reflects that no treatments are highly effective in all types of patients. With the advent of EBM, clinical researchers aimed to evaluate the effectiveness of various treatments by conducting clinical trials. This is far from trivial in tinnitus for several reasons ,9,10. FiMoreover, many efforts have been made to establish methodological standards for patient assessment, outcome measurement and clinical trial methodology in tinnitus ,14,15,16Box 1Pharmacological interventions.AntidepressantsAmitriptylineNortriptylineParoxetineSertralineTrimipramineAnticonvulsantsCarbamazepineGabapentinLamotrigineSelurampanelBenzodiazepines/GABAergic drugsAlprazolamBaclofenClonazepamDiazepamGlutamatergic drugsAcamprosateEsketamineMemantineNeremexaneMuscle relaxantsCyclobenzaprineEperisoneOrphenadrineTizanidineSodium channel blockerLidocaineOthersAtorvastatinBetahistineChinese medicineCilostazolCyclandelateDeanxitGinkgo bilobaMelatoninMisoprostol3,4-Methylenedioxymethamphetamine (MDMA)NaloxoneOdansetronOxytocinPiribedilPramipexoleVardenafilVitamin B12ZincNon-pharmacological interventions:Acupuncture/AcupressureAuditory TrainingBimodal stimulationVagus nerve stimulation plus sound therapyElectrical skin stimulation plus sound therapyElectrical tongue stimulation plus sound therapyBrain/neural stimulationTranscranial magnetic stimulationTranscranial direct current stimulationDirect electrical stimulationVagus nerve stimulationTranscutaneous electrical neural stimulationCombination ApproachesTinnitus Retraining Therapy (directive counselling plus sound therapy)Neuromonics (counselling plus acoustic stimulation)Electrical stimulation of the ear/cochleaCochlear implantsElectrical stimulation of the tympanum or the outer ear canalHearing AidsHyperbaric OxygenationLow-Level Laser TherapyMusic TherapyNeurofeedbackPhysiotherapyPsychotherapyCognitive behavioural therapy (group setting)Cognitive behavioural therapy Online/internet based Cognitive behavioural therapyMindfulness-based therapyHypnosisVirtual Reality based approachesSound TreatmentNoise generator (complete masking)Noise generator Enriched acoustic environmentFractal TonesTaylor-made notched music trainingCoordinated reset auditory stimulationHere we will discuss the translation of evidence into clinical guidelines in general and for the tinnitus field in particular. We will shortly review the current evidence and then focus on the challenges of guideline development in the tinnitus field and approaches how to address them.The first step is defining the clinical question, the relevant patient population, and the relevant outcomes. Based on a systematic literature search, the appropriate studies and systematic reviews of these are identified. Subsequently, the quality of evidence for all relevant outcomes is assessed. Systematic approaches to evaluate the level of evidence and the certainty of evidence have been developed. The certainty of evidence depends on the type of clinical trial and the methodological rigor of the trial. An example of a classification system of clinical trials according to the level of evidence is given in Evidence from randomized controlled trials starts at high quality, and evidence that includes observational data starts at low quality. The certainty in the evidence is increased or decreased by one or two levels according to further study criteria, resulting in a final level of certainty rating see .Bias occurs when the results of a study do not represent the truth because of inherent limitations in the design or conduct of a study. Risks of bias include sample selection bias  or funding bias (influencing the study design by a funder to achieve a particular outcome). Certainty in a body of evidence is highest when several studies show consistent effects. Conversely, certainty may be downgraded if the patients studied differ from those to whom the recommendation applies. The same is true if the setting of a study is different from the real-world condition .With the GRADE system , a transparent framework has been proposed for creating clinical practice recommendations. GRADE has four levels of evidence—also known as certainty in evidence or quality of evidence . The maiIn some circumstances, certainty in the evidence can be rated up see  when theA fair and balanced comparative evaluation of the efficacy and safety of various therapeutic interventions is challenging as the criteria for grading the evidence level are not equally applicable to different interventions. This can be best illustrated by the requirement of a control condition with a double-blinded group allocation of study participants. This may be feasible for a pharmacological intervention but impossible for testing a hearing device, counselling, or cognitive behavioral therapy. When testing these latter interventions, compromises in methodological quality must be accepted. However, comparing a certain intervention with a waiting list control group (ref) may favor this intervention when results are compared to an intervention tested in a placebo-controlled trial with effective blinding. Similar considerations are true for the assessments of the safety of therapeutic interventions. Whereas a thorough safety assessment is mandatory in pharmacological trials, side effects are only incompletely documented in trials that evaluate psychotherapeutic interventions .Moreover, the extent of tinnitus burden is strongly influenced by co-morbidities such as hearing loss, depression or anxiety . InterveIn this perspective paper, we aim to discuss the strengths and weaknesses of the current adaption of evidence-based medicine in tinnitus. For this purpose, we will summarize the currently existing guidelines based on a literature search and contrast them with each other and with the currently available evidence.As a first step, we aimed to identify published guidelines for tinnitus management. For this purpose, we have performed systematic literature research with the keywords “tinnitus” and “guidelines” in PubMed and Google, with the last update on 1 December 2022. To identify the evidence basis on which the guideline is based, we performed additional systematic literature research with the keywords “meta-analysis”, “tinnitus”, “Cochrane”, and “randomized controlled trials” in PubMed with the last update 1 December 2022. We then followed a hierarchical approach according to the established levels of evidence for therapeutic studies see . If therAs mentioned above, many different tinnitus treatments have been evaluated in clinical trials. In Tinnitus Counselling is typically considered a basic therapeutic approach. It is recommended by all guidelines, even if the evidence for the efficacy of randomized controlled trials is limited. Educational counselling was used as an active control condition in several studies, where it had a beneficial effect ,39. AddiCognitive behavioural therapy is the best-investigated treatment intervention for tinnitus. The main findings from a recent Cochrane meta-analysis  are thatMindfulness-based treatments are sometimes subsumed under CBT and included in systematic reviews of CBT. A recent systematic review focusing exclusively on mindfulness-based interventions (MBI)  concludeIn a large randomized clinical trial, patients were randomized into either a virtual reality (VR) based intervention or CBT, with both groups demonstrating similar improvement . These fAuditory treatments can be divided into four categories: devices for improving hearing, sound generators for tinnitus masking, auditory stimulation to induce specific neuroplastic changes in the central auditory system and auditory training.Concerning the improvement of hearing, there is meta-analytic evidence for the efficacy of cochlear implants on tinnitus in patients with unilateral severe hearing loss or deafness ,43. EvenSome forms of auditory stimulation, such as enriched acoustic environment ,47, amplAuditory training approaches encompass various training procedures, e.g., improving frequency discrimination, sound localization or signal in noise detection. In a systematic review, the quality of the studies investigating auditory training was rated low, and the need for appropriate RCTs was expressed .Tinnitus Retraining Therapy (TRT) consists of a combination of counselling and sound therapy. According to a recent meta-analysis , TRT as Various pharmacological agents have been investigated, and meta-analyses have been performed for several compounds. Most of these studies were negative. Exceptions are some experimental approaches, which cannot be performed as routine treatments because of side effects (Lidocaine), and some positive pilot studies ,56,57, wTinnitus activities treatment has not been investigated in controlled trials. There exists only one controlled trial in which tinnitus activities were the basis of treatment, and patients were randomized to additional sound therapy .Only pilot studies are available for neural therapy and botox ,65,66, wDifferent forms of physiotherapy have been investigated with promising results. Most of these studies focused on patients with tinnitus and comorbid temporomandibular joint or neck disorders. Large-scale randomized controlled trials are needed to determine which interventions are effective in which patient groups .Different neurobiofeedback paradigms have been investigated in several controlled studies, with promising results . HoweverMeta-analyses reveal positive effects for both transcranial direct current stimulation (tDCS)  and repeInvasive brain stimulation represents a highly experimental treatment requiring surgical insertion of electrodes under the skull. Epidural, subdural and deep brain stimulation has shown to be beneficial in case series, but there is far from sufficient data to support their routine clinical use .Different forms of bimodal stimulation have been investigated in the last years in randomized controlled trials. One involves the presentation of tones in combination with vagal nerve stimulation via an implanted vagus nerve stimulation device . Other aOf the many complementary and alternative therapies, only a few have been investigated in RCTs. The best-studied among these treatments is probably acupuncture, for which a recent systematic review identified 8 RCTs with 504 participants. Acupuncture had no significant effect on the primary outcome of the VAS score compared with control treatment but positive effects on secondary outcomes (THI and TSI score). However, the authors conclude that due to the low quality and small sample size of the included trials, the level of evidence is insufficient to draw any definitive conclusions .E-Health-based approaches involve online and offline-based treatments, including web-based– and smartphone apps. In particular, the number of smartphone apps for tinnitus management is rapidly growing , althougThe term “self-help intervention” is used in different contexts with different meanings. Whereas “self-help” traditionally means the mutual exchange of patients in self-help groups, the term “self-help” has been recently used in online-delivered CBT. A qualitative analysis of the traditional self-help concept revealed that members of self-help groups see the importance of their group primarily in social inclusion, psychosocial relief, coping with the disease and new insights into dealing with the disease. A systematic review of the traditional self-help approach concluded that because of the lack of high-quality and homogeneous studies, no confident conclusions could be drawn regarding the efficacy of self-help interventions for tinnitus .The evidence of the most widely used and investigated interventions and the respective recommendations in the various guidelines are summarized in There exist several guidelines for the management of tinnitus . They vaThe NICE Guidelines  were comThe German guideline was edited in 2021 by the German Society of Ear-, Nose- and Throat-medicine as an S3 Guideline , which mThe American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAO-HNSF) developed and published the US guideline in 2014 . I use aThe Swiss Guideline is a very short practice guideline, edited in 2019 by an association of networks of medical practitioners (Medix) [The European Guideline has not been edited by society but by a group of clinicians and researchers from different European countries who participated in the EU-funded COST Action TINNET . NeitherThe Japanese Clinical Practice Guideline for Diagnosis and Treatment of Chronic Tinnitus was developed by subcommittee members, edited by the Japan Audiological Society, authorized by the Oto-Rhino-Laryngological Society of Japan and published in 2019 . RecommeWe will first discuss the translation of the currently available clinical evidence into the different guidelines. In the second part, we will provide suggestions for further development.As mentioned above, the various existing guidelines differ in several aspects. This has many reasons. First, the guidelines differ in actuality and, thus, in the body of evidence based on their conclusions. Second, the methodological rigor, the systematics, and the transparency of how evidence was collected from the literature vary largely across guidelines. Third, the transition from evidence to recommendations is a process which involves subjective evaluations, considerations and balances and thus depends on the constitution of the guideline committee with their individual biases and conflicts of interest. All these factors may explain the variable interpretation of the evidence by different guidelines, which results in substantial variability across guidelines see . Sound tThere is a trade-off between the certainty of evidence  and the openness to innovation . However, with guideline update cycles of at least five years, it would take about ten years under optimal conditions for a new safe and effective treatment to be recommended in the guidelines. Furthermore, as a recommendation in guidelines plays a major role in the implementation of clinical practice and payment by healthcare providers, the question arises whether it can be justified that patients have to wait so long until they can benefit from an innovative therapy. Furthermore, from an economic perspective, earlier availability of effective, innovative treatments can reduce tinnitus’s enormous direct and indirect socio-economic costs ,87,88. FUndoubtedly, the methodology of evidence-based medicine (EBM) has improved the quality of medical services immensely. But EBM also has its inherent limitations and weaknesses. The methodological gold standard—studying a therapeutic intervention in many multi-centric randomized controlled trials and performing a meta-analysis of their results—aims to focus on the essential aspect of the pathological condition and the therapeutic intervention by removing all patient- and therapist-specific aspects by averaging across many patients and treatment settings. The more homogeneous the pathophysiology of a given disorder and the more homogeneous the intervention, the more appropriate this approach is. However, in the case of a heterogeneous condition such as tinnitus, this averaging approach has major limitations. Therefore, it is of utmost importance to identify criteria for meaningful tinnitus subtypes, as this would allow the investigation of specific interventions for these specific subtypes. The same applies to the heterogeneity of interventions. In neurostimulation, the investigated interventions vary in many parameters . TherefoFinally, it is remarkable that we could only identify guidelines from European countries, Japan and the US. This means that no guidelines are available for large parts of the world. Furthermore, as tinnitus suffering and coping also involve cultural aspects, it is questionable whether recommendations from Europe, Japan or the US can be applied to patients in other parts of the world.Although evidence-based medicine and the development of guidelines have made an important contribution to a scientific approach in medicine and the tinnitus field, one should be aware of their limitations and seek strategies to address them. As mentioned above, the guidelines committees, who translate the evidence from clinical trials into clinical recommendations, have a considerable margin of discretion. This aspect is particularly relevant in a highly multidisciplinary field like tinnitus, where audiologists, ENT specialists, general practitioners, neurologists, neurosurgeons, psychiatrists, psychologists and physiotherapists treat patients. Clinicians from different disciplines might be more familiar with the interventions in their discipline and might have an interest in placing them prominently in the guidelines. For example, a psychotherapist will have mainly experience with psychological treatment and be more in favour of it, whereas an audiologist is mainly familiar with sound-based interventions. Therefore, potential conflicts of interest of the guideline committee members are of utmost importance. In practice, the composition of guideline committees varies considerably.For some guidelines, the composition follows specific rules . In other guidelines, the committee comprises interested researchers or clinicians . Finally, in some guidelines, it is unclear how the committee has been composed . In the case of the NICE, the guidelines have been developed by a team from an institute specialized in quality assessment of clinical evidence. Typically, all committee members have to declare potential conflicts of interest. This helps to disclose financial or material interests. However, it becomes more difficult concerning immaterial conflicts of interest.Moreover, in most cases, there is no sufficient funding for guideline development. This might lead to the situation that guideline development is only possible by the voluntary commitment of experienced clinicians and researchers, who might not be experts in evidence-based medicine and may have an increased risk for material or immaterial conflicts of interest. In this context, sufficient public funding for guideline development is essential. Such funding enables the assessment of clinical evidence by an independent committee with experience in quality assessment, as is the case with the NICE guidelines. The lack of tinnitus-specific experience of such a committee might be compensated by inviting expert consultants in the guideline process. Whereas specialists in evidence assessment can ensure consistent criteria are applied for evaluating clinical studies of the various interventions, experts with tinnitus experience are needed to translate evidence to clinical recommendations. Independently of the composition of the guideline committee, all up-gradings and down-gradings of evidence see  must be As mentioned above, there is a certain trade-off between recommendations based on a huge amount of evidence collected over many years and the openness to innovation. Guideline committees should know this trade-off and consider that the evidence, especially for long-term outcomes, is naturally limited to innovative interventions. In such situations, the potential benefit of the innovation must be weighed against a certain amount of insecurity. Such situations might require adjustments of the criteria and thresholds for recommendation, as was the case in recommendations for newly developed mRNA vaccines during the SARS-2 COVID-19 pandemic. On the other hand, suppose guideline committees realize the potential of an innovative intervention but consider the available evidence for safety and efficacy as insufficient. In that case, recommendations for further research with specifications about the additionally needed information  is a much more constructive and innovation-friendly approach than just recommending against an innovative intervention. In this context, it is of utmost importance to stress that the patient’s interests should stand in the foreground and not the interests of the advocates for the established treatments, frequently constituting the guideline committees.An important limitation of the guideline process is the long delay between the publication of research data and their consideration in the guidelines. For example, the most recent US tinnitus guideline was published in 2014 and based on literature research from the spring of 2013. About half of the pub-med hits for “tinnitus randomized controlled trials” were published in 2013. This means the newer half of the relevant literature is not considered in the “actual” guideline. During the SARS-2 COVID-19 pandemic, the medical field has witnessed how fast medical progress can happen if needed. The living guideline process has been developed to cope with a particularly rapid increase in knowledge . This prSuch living guidelines, actualised in short cycles, also require innovative dissemination and communication methods, e.g., mobile app-based guideline versions  with sopA significant problem of the tinnitus field is the relatively low evidence level for most interventions. This is due to a lack of clinical trials with high methodological standards and small effect sizes for the various interventions. Many attempts have been made during the last decades to improve clinical trial methodology ,96,97,98Another aspect is the multidisciplinary nature of tinnitus management. To prevent a Maslow Hammer effect, in guideline committees and clinical management, it may be optimal to develop multidisciplinary tinnitus centers, where the cumulative knowledge of the different healthcare providers can be offered to the patient. A multidisciplinary tinnitus center where audiologists, psychologists, ENT specialists, general practitioners, neurologists, psychiatrists, neurosurgeons and physiotherapists can provide their expertise and evidence-based knowledge may be superior to a single specialist working in isolation. This may become ever more essential once subtyping makes the clinical management of the tinnitus patient even more complex. In situations where a multidisciplinary tinnitus clinic is not possible, developing a multidisciplinary network of practitioners can fulfil the same needs.Considering that the final goal of guidelines is a better treatment of patients with tinnitus, it is essential to understand patient values better, wishes and goals related to their clinical management. Even though organisations that develop clinical practice guidelines encourage the involvement of patients and the public in their development, there are no standard methodologies for doing so . A trialCurrently, tinnitus management varies widely across countries, disciplines, and institutions. In this context, developing treatment guidelines based on available evidence represents an important step towards a standardized treatment approach. We reviewed the evidence for various treatments and current tinnitus guidelines and concluded that the evidence-based treatment options are limited and, in many cases, unsatisfactory. Therefore, there is an urgent need to develop newer and better treatments for tinnitus. Guidelines are, by definition, conservative, as there is naturally more experience and, in most cases, more evidence for established treatments than innovative approaches. On the other hand, guidelines should not be hostile towards innovations. Here we propose strategies how to address this dilemma: (1) perform studies at higher methodological standards under consideration of the heterogeneity of tinnitus, (2) avoid a bias of the guideline committees towards established treatments, (3) formulate research needs instead of recommendation against intervention in case of insufficient data, (4) faster update cycles according to the living guideline concept and (5) more intensive involvement of tinnitus patients in guideline development. We are convinced that considering these aspects will make it possible to increase the quality standards of tinnitus management through evidence-based guidelines and, at the same time, create an innovation-friendly environment.Finally, we should not forget that the ultimate goal of the healthcare provider is to help the tinnitus patient. Guidelines are not ‘laws’, merely based on as much evidence as we currently have. The clinician treats individual patients and always has the therapeutic freedom to offer off-label treatments if their use can be justified. This option should not be dismissed if the quality of evidence is low for most current tinnitus treatments. For the individual case, chances of improvement, risks of treatment, alternative options, overall health state, psychosocial situation and the patient’s values and desires must be weighted in a holistic approach to make a reasonable clinical decision.


Hemostasis in ECMO and VAD was published in Frontiers in Medicine—Hematology that included six articles. As 4 years have passed since then, we have updated the series with eight articles addressing various aspects of extracorporeal membrane oxygenation (ECMO) and ventricular assist device (VAD) use. Conditions for use of ECMO such as sepsis and bridge to heart or lung transplant have been more commonly applied and has become a standard of care. ECMO cardiopulmonary resuscitation (ECPR) was initially used for selected patients with cardiac diseases; however, it is more widely used for patients who have cardiac arrest in the hospital or outside the hospital to save their lives regardless of the underlying condition. Recently, increasing number of institutions use bivalirudin as an anticoagulant for ECMO. ECMO is also used for patients with coronavirus diseases 2019 (COVID-19) for recovery from respiratory failure or bridge to lung transplant. In the setting of COVID-19, the duration of ECMO support for these patients was significantly longer such as months to more than a year. Use of VAD is also increasing, especially for the pediatric population, as the wait time for heart transplant is longer than adults. Moreover, some patients on VAD cannot be listed for heart transplant for certain underlying conditions, social reasons, HLA sensitization, or morbid obesity. For these indications, safe long-term anticoagulation and antiplatelet strategies are imperative. This updated series of articles provides the latest information in this area.In 2019, first series of Valdes et al. reported that bivalirudin might be a safe and cost-effective alternative to heparin in pediatric ECMO patients after review of seven articles. They concluded that use of bivalirudin as an anticoagulant for ECMO may reduce bleeding, transfusion requirements, and thrombosis with no difference in mortality. They suggested that multicenter studies are needed to compare bivalirudin vs. bivalirudin for ECMO anticoagulation.Neunert et al. also reported use of the direct thrombin inhibitors, focusing on bivalirudin, for pediatric ECMO. They compared the features of bivalirudin and heparin. They concluded that despite the limited data, there appears to be increasing evidence that bivalirudin may at least be an equally efficacious. Randomized controlled trials are extremely difficult in this diverse population of patients, continued data collection on the safety and efficacy of the use of bivalirudin in ECMO will be required.Wiegele et al. reported use of enoxaparin for patients with COVID-19 on veno-venous (VV) ECMO compared with unfractionated heparin. They concluded that enoxaparin was superior to unfractionated heparin in terms of thromboembolic primary and the hemorrhagic secondary endpoint by the retrospective findings.Olson et al. reported their experience in ECPR from a single center. There is growing evidence that ECPR improves survival and neurological outcomes in both in-hospital cardiac arrest and out-of-hospital cardiac arrest. Authors concluded that further randomized clinical trials are needed to identify the most appropriate ECPR candidates and optimal practice in order to conserve limited resources.Kalbhenn and Zieger stated the importance of “Treat Before They Bleed” approach and minimizing anticoagulation during VV ECMO. It is a strong and useful message for all clinicians that manage ECMO. They also emphasized the importance of the good availability of a coagulation laboratory.Regling et al. reported use of viscoelastic testing (VET) such as TEG™ and ROTEM™ for pediatric ECMO and VAD. It is not clear if VET alone is enough to monitor hemostasis and anticoagulation effect without conventional plasma based coagulation testing. Since studies of high quality data are limited, the authors concluded that further studies are needed.Opfermann et al. reported a prospective observational study on Multiplate™, ROTEM™, and thrombin generation assay (TGA) for left VAD. They showed that thrombin receptor activating peptide (TRAP)-induced platelet response on Multiplate™ and ROTEM™ in addition to the standard coagulation parameters might identify patients with platelet dysfunction and alterations of the primary hemostasis. However, TGA parameters were not different in total blood loss among groups of bleeding vs. non-bleeding.Schlagenhauf et al. reported that Heartmate 3 showed less thrombin generation than Heartmate II with comparable anticoagulation given. They concluded that thrombin generation assay is a useful tool to monitor the coagulation state of patients on VAD and guide anticoagulation.Hemostasis in ECMO and VAD, we are hoping that this series will be useful guides for daily clinical management on ECMO or VAD and future research.As the editors of the second series of JT wrote the text. JC and BZ reviewed the text and edited. All authors contributed to the article and approved the submitted version.


Ectocarpus has a haploid-diploid life cycle that involves the development of two multicellular generations: the sporophyte and the gametophyte. Each generation deploys a distinct developmental programme autonomously from an initial cell, the first cell division of which sets up the future body pattern. Here, we show that mutations in the BASELESS (BAS) gene result in multiple cellular defects during the first cell division and subsequent failure to produce basal structures during both generations. BAS encodes a type B″ regulatory subunit of protein phosphatase 2A (PP2A), and transcriptomic analysis identified potential effector genes that may be involved in determining basal cell fate. The bas mutant phenotype is very similar to that observed in distag (dis) mutants, which lack a functional Tubulin-binding co-factor Cd1 (TBCCd1) protein, indicating that TBCCd1 and PP2A are two essential components of the cellular machinery that regulates the first cell division and mediates basal cell fate determination.The first mitotic division of the initial cell is a key event in all multicellular organisms and is associated with the establishment of major developmental axes and cell fates. The brown alga  Summary: Protein phosphatase A, which regulates internal cell organisation in plants and animals, controls cell identity in a brown alga. highlighting functional conservation across a billion years of eukaryotic evolution. Arabidopsis, both the apical/basal axis and apical/basal cell identities are established at the time of the first cell division, and genetic analysis has identified two main pathways involved in this process  in basal and apical system fate determination . In contrast, the initial cell of the sporophyte generation undergoes a symmetrical initial cell division to produce two daughter cells with similar fates, both being components of the basal system EctocarpuEctocarpus mutant, distag (dis), with abnormal cellular features during the first cell division, and that was unable to develop basal systems   domain protein of the TBCCd1 class, with conserved roles in animals and plants (Earlier work identified an rophyte) . dis mutntrioles . The celd plants .BASELESS (BAS) locus in Ectocarpus. bas mutants exhibit phenotypes that closely resemble those of dis mutants, including an atypical initial cell division that leads to failure to deploy a basal system in the adult organism, increased cell size, abnormal cellular features, such as disorganised microtubule cytoskeleton, loss of bipolar germination and more extensive Golgi apparatus compared with wild-type cells. These phenotypic features are associated with modified patterns of gene expression during early stages of development. BAS encodes a protein phosphatase 2A regulatory subunit type B″ with EF-hand domains. Together, our results are consistent with BAS being involved in a pathway that plays a key role in initial cell division and basal cell fate determination during both the gametophyte and sporophyte generations of the Ectocarpus life cycle.Here, we report the identification of the Ectocarpus gametophyte generation, the two cells derived from the division of the initial cell develop as two germ tubes, and establish a rhizoid  and an upright filamentous thallus  (During the e organ) A,B. The e organ) C. These e organ) D,E.A screen of a large population of individuals mutagenised by ultraviolet (UV) irradiation identified two mutant strains  and baseless-2 (bas-2), respectively.In wild-type d plants , are prod plants E  was unaffected, whereas unilocular sporangia (where meiosis takes place) aborted and no functional meio-spores were produced, preventing the generation of gametophytes  exhibited a bipolar pattern of germination, with two germ tubes emerging from opposite poles of the initial cell , which is the stage at which conspicuous morphological differences were observed  and focused ion beam–scanning electron microscopy (FIB-SEM) were used to characterise further the cellular architecture of observed . This ispe cells .bas exhibited increased cell area compared with wild-type initial cells  was crossed with a wild-type female gametophyte  produced unilocular sporangia at maturity, suggesting a meiotic defect. Note that in Ec826, Ec827, Ec828 and Ec829, bas was the female partner, whereas in Ec830 and Ec831 it was the male that was bas. Therefore, the sexual background of the mutant did not change the meiotic defect. The lack of meiosis in heterozygous sporophytes precluded the analysis of any meiotic offspring to further investigate pleiotropy or additivity between DIS and BAS.The phenotypes of s mutant . The disrophytes , indicatbas-1 and bas-2 mutations (bas-1) and Ec801 (bas-2) mutant strains and the data compared with the wild-type Ectocarpus sp. strain Ec32 reference genome. More than 41,000 putative variants were detected for each strain. Those variants were compared with a list of 567,532 variants called during the analysis of 14 other mutant lines that showed a range of different phenotypes (bas-1 mutant (strain Ec800) and a G-to-A transition at position 2,807,321 in the bas-2 mutant (strain Ec801)  . The basanalysis .bas-1 mutation affects the first EF-hand, replacing a positively charged lysine residue with a negatively charged glutamic acid (K302E). This modification of electric charge may disrupt domain folding and/or function at least for the first EF-hand. It is possible that the bas-1 mutation leads to the production of a protein that is partially active. The bas-2 mutant carries a non-sense mutation that creates a premature stop codon at position 190 of the protein. This mutation is predicted to result in the production of a truncated protein that lacks both EF-hand domains  and had decreased in abundance about 1 week after germination, at the two- to five-cell stage  data  were anaerations A. The BAll stage . This paelopment .dis and bas mutants suggest that the products of the two genes may play roles in common cellular processes. We investigated the expression of DIS in a bas background, and, conversely, the expression of BAS in a dis background. We noticed that in a bas background, DIS expression in early stages (two to five cells) was significantly higher  and the prominence of the bas phenotype during the early stages of development, we focused on the two- to five-cell stage during germination of the initial cell. Given the subtle differences in phenotype between bas-1 and bas-2 (in particular the meiotic defect in bas-2), we also focused on comparing bas-1 and bas-2 transcriptional patterns.To characterise the bas-1 and bas-2 were comparable, and both were different from the wild-type samples  between bas-1 and wild type  (DE genes exhibited very similar patterns of up- and downregulation in the two d genes) .bas-1 compared with wild type had, globally, lower expression levels in bas-2, and upregulated genes in bas-1 were slightly more expressed in bas-2  than bas-1   . In termin CDSs) . The onlbas mutants, whereas upregulated genes in mutants were associated with intracellular protein transport transcription and protein synthesis (bas mutation (see above). Using the HECTAR predictor  transcription factors in Ectocarpus are differentially expressed in the bas-2 mutant compared with wild type (Gene Ontology (GO) term enrichment analyses of DE genes revealed that functions related to photosynthesis and metabolism were downregulated in both ynthesis . The dowredictor , we examproteins , which, ild type .bas-1 and bas-2, respectively, compared with the wild type (i.e. genes that had 0 transcripts per million in wild-type samples). Seventeen genes were silenced in the bas-1 and 29 in bas-2 compared with wild type  initial cell division and, at later stages of development, during meiosis. However, no cellular defect was observed prior to initial cell divisions, suggesting that BAS operates only after release of the initial cells from the reproductive structures. The meiotic defect observed in the bas-2 mutant and in heterozygous sporophytes produced from dis×bas-2 mutants suggests that the BAS protein may have also a role during meiotic cell division. The absence of this meiotic defect in the bas-1 may be explained by the production of a protein with sufficient activity in bas-1 to ensure its role during meiosis but not during the first cell division. Higher penetrance of the bas-2 mutation is also indicated by the greater proportion of differentially expressed genes in bas-2 compared with bas-1. Indeed, about 40% of the genome was significantly mis-regulated in the bas-2 mutant during early stages of development, demonstrating that mutations at the BAS locus can lead to broad, large-scale modifications to the transcriptome. It is interesting to note that half of the bZIP transcription factors of Ectocarpus are differentially expressed in bas-2 compared with wild type. This observation suggests that BAS may be part of a pathway involving additional regulatory proteins that drives the establishment of the apical-basal axis during the early development of Ectocarpus.The two Ectocarpus BAS is predicted to encode a PP2A phosphatase regulatory B″ subunit. In animals, PP2A phosphatases are involved in diverse cellular processes and constitute a major component of cellular serine/threonine phosphatase activity, dephosphorylating several hundred cellular substrates  interacts with bZIP transcription factors, and is implicated in leaf and root development as well as mechanical stress response (Arabidopsis (Ectocarpus BAS protein is related to the Arabidopsis FASS/TON2 protein but is orthologous to the AtB″-δ/ε protein mentioned above (At5g28900/At5g28850). The microtubule phenotype we describe here, in which PP2A B″ disruption in brown algae is associated with microtubule disorganisation, may further underline a conserved role for PP2A across plants and brown algae.Consistent with a conserved role for PP2A in development across multicellular eukaryotes, the response . The PP2response . PP2A inbidopsis . The EctFucus zygote polar axis prior to the first cell division  rhizoid, directly linking intracellular Ca2+ signalling and acquisition of basal cell identity. In this context, we speculate that the BAS protein may be a potential sensor of a pre-germination Ca2+ signal.In animals, the B″ class of PP2A B subunit is thought to be involved in Ca domains . Note thbas and dis mutant strains, suggesting that BAS and DIS may be involved in similar cellular processes. However, some differences between the mutants are also apparent, such as the less marked Golgi fragmentation and no effect on nuclear positioning in early stages of development in bas, and also a meiotic defect was only observed in bas-2.Similar morphological and cellular phenotypes were observed for DIS is predicted to encode a TBCCd1 protein. This protein shares similarity with TBCC, which is a component of the complex (TBCA to TBCE) that mediates dimerisation of α and β tubulin subunits to form microtubules  phenotypes of the bas and dis mutants are a consequence of cellular defects during the first cell division, perhaps through disruption of the distribution of hypothetical cell fate-determining factors during this critical step of development  was crossed with the outcrossing line Ec568 to generate a segregating population of 38 individuals. Each of the 38 individuals was derived from a different unilocular sporangium . The meio-spores germinated to produce gametophytes, which were isolated and allowed to produce gametes that germinated parthenogenically. The resulting partheno-sporophytes were then observed under a light microscope to determine whether they exhibited the bas phenotype. The presence of the bas-1 mutation was determined by Sanger sequencing of PCR products  for each of the 38 individuals. The bas-2 mutant (Ec801) was not usable for crosses because it did not form functional unilocular sporangia, which are required for gametophyte production.Genetic crosses were performed as described by Ectocarpus sp. reference genome (http://samtools.github.io/). These variants were compared with a list of variants identified in genome sequence data for 14 other Ectocarpus mutant lines in order to remove false-positive mutations caused by, for example, errors in the reference genome sequence.Genomic DNA from Ec800 and Ec801 strains was sequenced on an Illumina HiSeq4000 platform . After quality cleaning using Trimmomatic , the reae genome  using Boe genome . CoveragVariants unique to strains Ec800 and Ec801 were quality filtered based on coverage depth (±50% of the genome mean), mapping quality (>20), variant quality (>50), variant frequency (>0.9) and variant support in both sequencing directions. A custom Python script allowed the identification of variants in CDSs and the effect of each CDS mutation on the predicted protein was accessed manually . A schemEctocarpus samples were processed as described  and hemicellulase (4% w/v) for 1 h, and the preparation was then rinsed with PBS and blocked overnight in 2.5% non-fat dry milk in PBS. Samples were treated with an anti-tubulin antibody  at 20°C overnight and then treated with the secondary antibody  at 20°C overnight. The preparation was rinsed with PBS and blocked overnight in 2.5% non-fat dry milk in PBS and then treated with an anti-centrin antibody  at 20°C overnight, followed by the secondary antibody  for 8 h. Samples were stained with 4′,6-diamidino-2-phenylindole  for 10 min at room temperature and mounted in ProLong Gold (Invitrogen).escribed  using a xyz). The z-stack height fitted the specimen thickness. A two-step sequential acquisition was designed to collect the signal from three or four channels. The first step recorded the anti-tubulin fluorescence signal  and the transmitted light. The second step acquired the DAPI fluorescence signal . Signal intensity was averaged three times. Fiji software was used to optimise the raw images, including maximum intensity projection and de-noising (3×3 median filter). For any given data, both wild-type and mutant images were analysed simultaneously with similar settings.Confocal microscopy was conducted using an inverted SP8 laser scanning confocal microscope (Leica Microsystems) equipped with a compact supply unit which integrates a LIAchroic scan head, several laser lines (405 and 488 nm), and standard photomultiplier tube detectors. We used the oil immersion lens HC PL APO 63×/1.40 OIL CS2. The scanning speed was set at 400 Hz unidirectional. The pinhole was adjusted to one Airy unit for all channels. The spatial sampling rate was optimised according to Niquist criteria, generating a 0.058×0.058×0.299-µm voxel size . The film was cut into <1-cm side triangles, and these were attached to Petri dishes by adhesive tape. Plurilocular structures, which were attached to the triangles, were rapidly immersed in liquid propane cooled to −180°C by liquid nitrogen, and immediately transferred into liquid nitrogen. The samples were submerged in substitution solution containing 2% osmium tetroxide with acetone at −80°C for 2 days, −40°C for 2 h and 4°C for 2 h. Finally, the temperature of the samples was gradually allowed to rise to room temperature, and they were then washed with acetone several times. The gel support films were infiltrated and embedded in Spurr's low-viscosity resin (Polysciences) on aluminium foil dishes. The films with the samples were turned inside out on the upper surface of the resin. Serial sections were cut with a diamond knife using an Ultracut ultramicrotome (Reichert-Jung) and mounted on Formvar-coated slot grids. Sections were stained with TI blue (Nisshin EM) and lead citrate and observed using an electron microscope .Medium containing mature 4 and 0.1% uranyl acetate in acetone containing 5% H2O as substitution medium (For TEM coupled to focused ion beam-scanning electron microscopy (FIB-SEM), freshly released gametes were collected in cellulose capillaries and cultivated in the capillaries in Provasoli-enriched seawater for 3-5 days at 14°C in the dark or approximately 1 day at 14°C in a 12 h light/12 h dark regime to produce two- to five-cell stage partheno-sporophytes. Cells in capillaries were frozen at high-pressure , freeze-substituted  with 0.2% OsOn medium  and embeIn order to identify a region of the sample containing algae at high density for FIB-SEM data acquisition, a 3D X-ray tomogram of the resin block was acquired with a Bruker Skyscan 1272. The region of interest was exposed using a 90° diamond trimming knife  mounted on a Leica UC7 ultramicrotome. The sample was then attached to a stub using conductive silver epoxy resin (Ted Pella) and gold sputter coated (Quorum Q150RS).bas-2 cells, and chose a representative image to present in https://bio3d.colorado.edu/imod/), MIB  for sample preparation and acquisition. After the deposition of a protective platinum coat on the surface above the region of interest, a 60-µm-wide trench was opened to identify and image several cells in parallel. During the stack acquisition, FIB slicing was performed at 30 kV and 700 pA current. The datasets were acquired at 8 nm isotropic voxel size with the SEM at 1.5 kV and 700 pA current, using a back-scattered electron detector (ESB). After acquisition, the image stacks were acquired using the Fiji plugin ‘Linear stack alignment with SIFT’ . We acqud/), MIB  and AMIRMultiple alignments were generated with Muscle in MEGA7 . PhylogeBAS and DIS genes were investigated using TPM values obtained after kallisto pseudo-mapping and calculation of the lengthScaledTPM using the tximport package in R . Previously generated RNA-seq data for wild-type and dis samples  and mutliQC (v. 1.9). Raw reads were trimmed and filtered based on quality score, and adapter sequences were removed using Trimmomatic (v0.39). Transcript abundance was evaluate using kallisto (v0.46.2) via pseudo mapping on CDS features. The matrix of counts and TPMs for all samples and all replicates were generated in R using the tximport package.P-value below or equal to 0.01. Genes were considered to be exclusively (uniquely) expressed in bas mutants when they were significantly upregulated compared with wild type and the wild-type mean TPM was equal to 0. Conversely, genes were considered to be specifically silenced in bas mutants when they were significantly downregulated compared with wild type and their TPM means were equal to 0.A gene was considered to be expressed if the TPMmean was above the 5th percentile as in . About 4GO term and HECTAR localisation enrichment were carried out in R using the ‘clusterProfiler’ package .Click here for additional data file.10.1242/develop.201283_sup1Supplementary informationClick here for additional data file.


This systematic review evaluated the quality of evidence for the prevention and management of facial pressure injuries in medical staff.This review was presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines.We retrieved the relevant studies from 19 databases. Using the literature evaluation standards and evidence grading system of the Australian Joanna Briggs Institute Evidence‐Based Health Care Center, we evaluated the quality of the literature encompassing different types of research and assessed their levels of evidence.A total of 13 studies were included, including seven expert consensuses, two recommended practices, one clinical decision, one best practice information booklet, one systematic review and one randomized controlled trial. In the end, 31 best evidence were summarized, including skin cleaning and care, PPE placement and movement, reasonable use of dressings, treatment measures and education and training. On 12 January 2020, the World Health Organization (WHO) named the disease coronavirus disease 2019 (COVID‐19) , Fortunately, if appropriate measures are taken, the facial and ear injuries that medical staff are most vulnerable to can also be prevented. A parallel double‐arm randomized clinical trial compared the use of foam and extra‐thin hydrocolloid dressing by medical staff working at the forefront of the fight against COVID‐19 to prevent PPE‐induced facial stress injuries  providing references for clinical practice in the prevention and management of facial pressure injuries in medical staff, (2) reducing the incidence of such injuries and (3) improving the facial comfort of medical staff. To this end, we collected and evaluated the evidence obtained through evidence‐based nursing methods and summarized the findings.22.1We used the problem development tool of the population, intervention, professional, outcome, setting and type of evidence (PIPOST) model of the Joanna Briggs Institute (JBI) Evidence‐Based Health Care Center to construct evidence‐based problems. The first ‘P’ (population) is the target population for the application of evidence. This includes medical personnel working at the frontlines in the fight against COVID‐19, those working in fever clinics and those who go out for batch nucleic acid testing or to infection wards and need to wear protective equipment. ‘I’ (intervention) is the recommended intervention. This includes the prevention and management of facial pressure injuries caused by the use of protective equipment. The second ‘P’  is the implementer of evidence application, that is, medical staff. ‘O’ (outcome) is the outcome indicator, which is the alleviation of facial pressure injury and restoration of facial comfort. ‘S’ (setting) is the evidence application site, that is, anti‐epidemic frontline, fever clinic, nucleic acid testing site or infection ward. ‘T’ (type of evidence) is the type of evidence resource, which includes guidelines, expert consensus, clinical decisions, recommended practices, best practice information booklets, systematic reviews, evidence summaries and randomized controlled trials (RCTs).2.2According to the ‘6 S’ pyramid evidence model, we searched the following databases: British Medical Journal Best Practice, UpToDate, the Guidelines International Network, the National Institute for Health and Care Excellence, the Scottish Intercollegiate Guidelines Network, the Registered Nurses Association of Ontario, the European Pressure Ulcer Advisory Panel, the New Zealand Wound Care Society, the American Academy of Dermatology Association, the European Academy of Dermatology Association, the Cochrane Library, JBI, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, SinoMed, PubMed, the China National Knowledge Infrastructure database, Wanfang databases and the Chinese Scientific Journal Database. The search keywords used were as follows: ‘pressure ulcer’ ‘device‐related pressure ulcer’, ‘MDRPI’, ‘MDRPU’, ‘facial skin injury’, ‘PPE‐related tissue damage’, ‘COVID‐19‐related pressure injury’, ‘skin lesion’, ‘facial injury’, ‘personal protective equipment’, ‘COVID‐19’, ‘ “SARS‐CoV‐2,” ‘Coronavirus Disease 2019’ and ‘COVID‐19 Pandemic’. The article types searched were guidelines, expert consensus, clinical decisions, recommended practices, best practice information booklets, systematic reviews, evidence summaries and RCTs. The retrieval period was from 1 January 2010 to 23 October 2021.2.3The inclusion criteria were as follows: (1) the research object was medical staff; (2) the research was aimed at the prevention and management of facial pressure injuries; (3) the types of reports included were guidelines, expert consensus, clinical decisions, practice recommendations, best practice information booklets, systematic reviews, evidence summaries and RCT findings; and (4) the language was Chinese or English.The exclusion criteria were as follows: (1) duplicate publications; (2) studies with original text unavailable; and (3) studies with unqualified quality evaluation.2.42.4.1The literature quality evaluation was independently completed by two authors. For training, these authors had enrolled into and completed the Evidence‐Based Nursing Practitioner Training Class of the JBI Evidence‐based Nursing Cooperation Center of Fudan University. If there was a disagreement, the two authors tried to resolve their disagreements by discussion, and if they could still not reach a consensus, they invited evidence‐based nursing experts and evidence‐based training instructors to make a judgement after thorough discussion.2.4.2The quality evaluation standard of guidelines adopted the Appraisal of Guidelines for Research and Evaluation Instrument  was evaluated as ‘No’, and the remaining items were evaluated as ‘Yes’. In the remaining one expert consensus, (American Academy of Dermatology Association (AAD), Is there a reference to the extant literature?) and 6  were evaluated as ‘No’, and the remaining items were evaluated as ‘Yes’.Items were from the evaluation standard of the Australian JBI Evidence‐Based Health Care Center (2016). We included seven expert consensuses  was evaluated as ‘Not applicable’, and item 9 (Was the likelihood of publication bias assessed?) was evaluated as ‘No’. The remaining items evaluated as ‘Yes’.Items were from the evaluation standard of the Australian JBI Evidence‐based Health Care Center (2016). We included one systematic review , 8 , and 11 (Were outcomes measured in a reliable way?), the evaluation was ‘Unclear’. For item 9 , the evaluation was ‘No’, and for the remaining items, the evaluation was ‘Yes’.Items were from the evaluation standard of the Australian JBI Evidence‐based Health Care Center (2016). A randomized controlled study  was evaluated as ‘No’, and the rest of the items were evaluated as ‘Yes’. The quality evaluation result for the expert consensus item 6  was ‘No’, and the rest of the items were evaluated as ‘Yes’. The quality evaluation result of the RCT for item 5 (Were those delivering treatment blind to treatment assignment?) was ‘No’, and the rest of the items were evaluated as ‘Yes’. The quality evaluation result of the quasi‐experimental study was ‘Yes’ for all items. The quality evaluation results of the cohort study for items 9  and 10 (Were strategies to address incomplete follow up utilized?) were ‘Unclear’. The remaining items were evaluated as ‘Yes’.Items were from the evaluation standard of the Australian JBI Evidence‐based Health Care Center 2016). In this study, we included two recommended practices  and Military Biosafety Reach Special Project (20SWAQK48) in China.The authors declare that they have no conflict of interest.


Patient value is an important factor in clinical decision making, but conventionally, it is not incorporated in the decision processes. Clinical decision making has some clinical guidelines as a reference. There are very few value-based clinical guidelines, but knowledge about how values affect decision making is mentioned in some scattered studies in the literature. We use a literature review method to extract evidence and integrate it as part of the decision-making model. In this paper, a value-based therapy recommendation comprehensive model is proposed. A literature analysis is conducted to collect value-based evidence. The patients’ values are defined and classified with fine granularity. Categorized values and candidate therapies are used in combination as filtering keywords to build this literature database. The literature analysis method generates a literature database used as a source of arguments for influencing decision making based on values. Then, a formalism model is put forward to integrate the value-based evidence with clinical evidence, and the literature databases and clinical guidelines are collected and analyzed to populate the evidence repository. During the decision-making processes, the evidence repository is utilized to match patients’ clinical information and values. Decision-makers can dynamically adjust the relative importance of the two pieces of evidence to obtain a treatment plan that is more suitable for the patient. A prototype system was implemented using a case study for breast cancer and validated for feasibility and effectiveness through controlled experiments. Clinical decision making is a complex process that involves numerous factors, including clinical evidence, patient values, and healthcare professionals’ expertise . ClinicaThe recommendation of treatment plans has traditionally been explored in the realm of representing and interpreting clinical guidelines. John Fox and his colleagues proposed PROforma, which is a formalism that offers an evidence-based and objective tool for selecting treatment plans and providing decision support. Its main goal is to empower clinicians with optimal treatment recommendations . SystemsIn addition to PROforma, several studies have explored alternative methods and techniques for recommending treatment plans. Romina et al. examined the interpretation and utilization of clinical practice guidelines or recommendations . Some rePatient values refer to the individual beliefs, preferences, desires, and priority considerations that patients have regarding their habits, health, and medical decisions. Healthcare professionals need to take into account not only clinical evidence and best practices but also the patient’s values when making medical decisions. Patient-centered medical decision making is crucial because certain treatment options that threaten the patient’s valued beliefs may directly reduce the patient’s adherence to the treatment plan, leading to suboptimal treatment outcomes. Berry et al. outlined six categories of patient values, including activities, abilities, possessions, principles, emotions, and relationships . These vThere is a growing trend of incorporating patient values into Clinical Decision Support Systems (CDSSs) using methods such as Patient-Reported Outcome Measures (PROMs) and Shared Decision Making (SDM) ,9. PROMsNumerous studies have investigated the integration of values into medical decision support systems. Wherton et al. developed a value-based medical decision support system that aids doctors in comprehending patients’ values and needs . Liu et NICE clinical guidelines mention treatment side effects that may challenge patient values but lack standardized analysis . IntegraIn summary, while certain studies have introduced the concept of patient values into clinical decision making and developed models that incorporate patient values, there remains a lack of systematic utilization of values to establish concrete evidence of their influence on medical decision making.Literature analysis is a widely adopted research method that facilitates the systematic collection, organization, evaluation, and synthesis of the literature, enabling the exploration and examination of the current state, trends, and issues within a specific research field. This methodology finds applications in various domains, including medicine, social sciences, and education. For instance, Porr et al. employed a literature analysis to investigate the ethical challenges confronted by nurses in long-term care facilities when providing care for individuals with dementia  Hsieh etThere may exist implicit mapping relationships between treatment plans and values, which are often not explicitly addressed in clinical guidelines. It is hypothesized that these relationships can be supplemented by analyzing the clinical decision literature using a literature analysis approach, incorporating relevant references to inform the decision-making process. Patient values can be influenced by diverse factors, including cultural background, beliefs, social environment, educational background, and personal experiences. By systematically collecting, organizing, and analyzing the relevant literature, a deeper understanding of patient needs and values can be attained, facilitating the development of treatment plans that better align with patient requirements. Through a literature analysis, the objective is to establish a foundation of arguments centered on patient values. We are committed to integrating objective clinical knowledge with patient values into the clinical decision-making process to find the most suitable treatment plan for patients. We use a literature analysis method to extract evidence of the impact of values on decision making from the literature and, using scientific research methods, integrate this value evidence with relevant clinical data into a comprehensive evidence base to guide patient clinical decision making. The comprehensive evidence base provides interpretable treatment recommendations and has traceability. We recognize that due to the diversity of patient values and diseases, the resulting evidence base may have certain limitations. We follow the following standards and ideas: In the research process, we focus on a literature analysis related to breast cancer, looking for key sentences that influence decision making by values and forming an evidence base for decision making influenced by values. By analyzing the structure of this evidence base and the clinical decision-making evidence base, and using matching algorithms to match patient information with evidence, we will provide treatment options that integrate patient values.We categorize the objectives of this study into the following three goals:Goal 1: Summarize a knowledge base by searching for research on the impact of values on decision making in the current clinical literature .Goal 2: Construct a unified model that can accommodate both clinical evidence and value-based evidence to provide systematic support for decision-makers .Goal 3: Evaluate the feasibility and effectiveness of a unified model for decision-making evidence .Box 1The NICE guideline suggests that when a patient’s indicator is ER+, both chemotherapy and endocrine therapy can be offered as treatment options. According to the medical literature, when a patient’s indicator is ER+ and the patient places more emphasis on treatment duration, chemotherapy may be more advantageous than endocrine therapy.Due to the current clinical guidelines’ limited consideration of patient values and the lack of connection between patient values and systematic clinical decision making, our goal is to integrate the clinical evidence model and the value-based evidence model into a comprehensive evidence framework. We have taken advantage of the research features of both review articles and scientific papers. This involves extracting evidence of patient values from the literature and objective clinical evidence from clinical guidelines, merging them into a unified evidence repository. This evidence repository will encompass both clinical knowledge and value-based knowledge. The current clinical guidelines and literature summaries are shown in the Collecting clinical evidence and conducting model analysis  and developing a model (detailed in Constructing a unified model for decision evidence (UMDE) . The system is designed to collect clinical information and values from patients with clinical information stored in key–value pairs to create a comprehensive collection of patient clinical data. By employing a series of guided questions, we obtain patients’ clinical information, occupational and personalized values. The patients’ value list comprises a predefined set of occupational values, which are each assigned a weight ranging from 0 to 1. Both clinical and value information can be added or adjusted by the patients, ensuring that the system captures information that better reflects their specific circumstances, thereby enabling more tailored recommendations. In our recommendation module, we have introduced sliders for patients and doctors, enabling them to adjust the weights and proportions of clinical and value perspectives. This empowers them to tailor the overall balance according to their individual needs. The effectiveness of the model is demonstrated in In the left part of In the left part of Once the patients’ clinical and value information is collected, the matching of arguments is performed using Algorithm 1, resulting in sets of activated arguments and their corresponding weights. The process is illustrated in the right part of We invited 90 patients, 5 expert doctors from hospitals, and 10 medical students to participate in our evaluation experiment. We prepared a CDSS that considers only the objective symptoms of patients . The OCDSS relies solely on clinical guidelines to analyze patients’ objective symptoms and recommend treatment plans. Both the OCDSS and VICDS share the same clinical evidence database. The 90 patients were evenly divided into three groups, where the expert doctors made treatment decisions for the patients using traditional medical methods , OCDSSs, and VICDSs, respectively.Box 2Satisfaction level with the chosen decision-making plan What were the unacceptable situations during this treatment? (text)Which values were threatened? (text)Which values were protected? (text)Doctor survey:Satisfaction level with the chosen decision-making plan Smoothness of the current patient’s treatment Patient survey:In order to facilitate the evaluation of three treatment recommendation models, we conducted a preliminary survey of each volunteer before the experiment and recorded their clinical expectations for treatment outcomes. Since treatment is a long-term process, we used two survey questionnaires to collect patient satisfaction, and the patient’s primary physician also completed two satisfaction questionnaires at different stages of treatment. The specific survey questionnaires are shown in the text We obtained the statistical data from two stages of survey questionnaires, as shown in In the OCDSS experimental group, patient satisfaction also decreased from the first stage to the second stage, but overall satisfaction was higher compared to the DOCTOR experimental group. Some doctors expressed that having clinical knowledge helped them become more aware, which was considered a positive experience.We found that the VICDS experimental group had higher levels of satisfaction among both doctors and patients, and there was a significant improvement in achieving the expected treatment outcomes. Through interviews, we learned that incorporating values in clinical decision making allowed patients to better uphold their own values, make better-balanced decisions when considering interpretive arguments, and prepare mentally or practically in advance when certain values might need to be compromised. Expert doctors stated that although incorporating values increased the complexity of decision making, patient treatment compliance improved significantly, which was a major reason for the substantial improvement in treatment outcomes. Systematized knowledge helped doctors gather more information and make reasonable decisions in collaboration with patients.The findings revealed a high consistency between VICDS recommendations and patients’ reselection of treatment plans. The VICDS takes into account both patients’ objective symptoms and their values, which influence their treatment decisions. Patients can weigh the affected values mentioned in the recommendations, helping them prepare for potential sacrifices. Some differences in recommendations were observed, which were attributed to certain patients’ values not being systematically validated in published papers, leading to deviations in the results. Additionally, the study’s scope may not have covered all of the relevant literature, which could also contribute to discrepancies. Patients’ actual treatment choices without using the VICDS tended to focus more on objective symptoms, overlooking the impact on values, potentially resulting in less suitable treatment plans.Currently, medical technology is highly advanced, offering numerous treatment options for various diseases. However, due to the long update cycles of medical guidelines, there is often a lack of deliberate collection of information related to patients’ values in these guidelines. Patient-centered treatment approaches have not been fully incorporated into medical guidelines, and only a small fraction of articles from Narrative Reviews are likely to be included in the guidelines.Therefore, we emphasize the importance of patient involvement in decision making and explore personalized preferences and expectations of patients regarding treatment choices. Our research aims to incorporate patients’ values into the clinical decision-making evidence, leading to the development of the VICDS. Through the VICDS, we collect and integrate information from patients, considering their potential challenges and hesitations, and quantitatively store this data. By matching real patient information with evidence containing values and utilizing algorithms, we comprehensively rank treatment options, shifting the focus of healthcare toward patients. This approach provides valuable supplements to medical guidelines concerning decision making based on values and offers support and evidence for clinical decisions.We conducted the tracking and recording of the treatment processes for three groups of volunteer patients and collected data on satisfaction and treatment outcomes. The results show that using the clinical decision support system provides doctors and patients with systematic clinical evidence supplements. Compared to not using the clinical decision support system, there is a slight increase in patient and doctor satisfaction and improved clinical treatment outcomes. The inclusion of patient values shifts the decision-making center toward patients, and doctors can incorporate patients’ values into their considerations through system prompts. Patients find that using the VICDS for decision making allows them to weigh the evidence presented and make well-informed psychological preparations and lifestyle adjustments.This study makes three main contributions with the aim of providing comprehensive and personalized support for decision making in specific disease domains.Firstly, medical objective factors such as diseases and treatment plans are acquired from medical clinical guidelines. An online literature database is screened and analyzed using disease names, treatment plans, and values as keywords. Through this process, a Value-Based Evidence Database (VBED) is constructed, encompassing the relevant literature in the specific disease field where values influence decision making. The importance of values in the decision-making process is considered, ensuring that the database covers not only objective medical guidelines but also the impact of values.Secondly, the evidence database of how values influence decision making is analyzed and formalized. The goal is to unify value-based evidence with objective evidence, establishing the Unified Model for Decision Making with Values (UMDE). Through this unified model, healthcare professionals and patients can better understand and balance different factors when making treatment choices.Thirdly, a prototype system called the VICDS is designed and implemented. The VICDS matches patient information with the unified evidence and provides comprehensive and personalized treatment recommendations. Leveraging the information in the database and the structure of the model, the VICDS considers individual patient needs and values, offering customized advice for each patient. This approach aims to enhance the treatment experience for patients and facilitate better treatment outcomes.In summary, this study contributes by constructing a Value-Based Evidence Database, unifying objective evidence with value-based evidence, and designing a prototype system that provides comprehensive and personalized treatment recommendations for patients. These contributions aim to provide healthcare professionals and patients with more comprehensive and accurate information for decision making in specific disease domains, thereby promoting better treatment decisions and outcomes. We acknowledge that the VICDS currently has certain limitations and shortcomings. Firstly, the influence of values on the decision-making evidence database is somewhat limited due to the current scarcity of evidence, with a predominant focus on breast cancer. This represents a notable constraint of the VICDS at present. Secondly, the diversity of population-based pre-configurations is restricted by the limited diversity in sampling and statistics across different regions, potentially introducing some region-specific biases. Moreover, the sample size may not be extensive enough, leading to a potential lack of precision in mapping the values of the population. To address this, continuous data acquisition is essential to enhance the accuracy of the pre-configurations. Lastly, in the final recommendation results page, the VICDS primarily emphasizes the overall ranking of treatment plans without providing a specific comparison of the advantages and disadvantages between individual plans.This study uses disease names, treatment plans, and values as keywords for a literature analysis to construct a value evidence database in a certain disease field where values influence decision making. By analyzing the value evidence database and formalizing it, the goal is to unify it with objective evidence. The unified evidence is used to provide patients with comprehensive decision making.The correlation of the factors that influence values with treatment plans was made, and evidence of patient values was established based on literature analysis.A unified formalism of value-based evidence and clinical evidence was developed.A running CDSS prototype for breast cancer was built on top of the unified formalism, and its feasibility and effectiveness were evaluated.The contributions of this article are as follows:In the future, we will utilize more real-world cases to optimize our preset values. Simultaneously, we will refine our question–answer guidance through feedback from patients and doctors, fully exploring patient information to enhance user experience. Additionally, we aim to establish relevant knowledge graphs to explore the application of Markov Ontology Theory in calculating weights. We will explore the incorporation of value-based decision evidence into local treatment plans, but this may introduce fairness concerns in overall treatment plan rankings. Therefore, one of our future research goals is to explore alternative methods to mitigate the impact on fairness and seek further improvements.Moreover, we also plan to explore the following directions in future research: firstly, identifying the relative importance of values in different disease domains and quantifying them concretely; secondly, investigating which disease domains can be validated earliest with the proposed methods; thirdly, providing a value-based evidence repository influencing decision making for more disease domains, applying the algorithm to a broader range of diseases, and validating its applicability and effectiveness across different diseases; and fourthly, exploring whether the methods and systems mentioned in this paper can be integrated with others to ultimately achieve more meaningful advancements in the medical field.We will strive to diversify our projects further to refine and expand the proposed system prototype, providing comprehensive and effective support for future medical decision making and treatment choices.


In their commentary, Ellen and Ben-Sheleg highlighted the need for doing more in the field of evidence-informed policy-making (EIPM). They emphasized the importance of monitoring and evaluating EIPM activities and the need to do more to take the field to the next level. The authors were encouraging a more innovative approach to evaluate the impact of EIPM, to avoid reinventing the wheel and bring more from relevant fields like behavioural economics, psychology, and marketing in getting the individuals and organizations to change their behaviour, and upscaling the opportunity that has been offered by the coronavirus disease 2019 (COVID-19) pandemic. The commentary also suggested developing a gradient to prioritize which issue of healthcare concerns could be solved through evidence-informed policy. While this idea might be fascinating to increase policy-makers’ buy-in, it also encourages us to ask whether we can ever say that we have done enough in the EIPM field. We need to ask if EIPM can ever be 100% evidence-based as Ellen and Ben-Sheleg have tried to. How to be strategic in selecting which healthcare issue to solve? What is the importance of the context when creating short-term wins? And what are the special characteristics of the health sector that need to be considered when borrowing from other field into the EIPM?1 In 2021, COVID-END convened the Global Commission on Evidence to Address Societal Challenges to change the global panorama on evidence generation. This led to the publication of a report titled “A wake-up call and path forward for decision-makers, evidence intermediaries, and impact-oriented evidence producers.”2 In addition, Cochrane published “Cochrane Convenes: Preparing for and responding to global health emergencies. Learnings from the COVID-19 evidence response and recommendations for the future.”3 Cochrane brought together leaders in health research and health evidence to explore and recommend the changes needed in evidence synthesis to prepare for and respond to future global health emergencies. These are a few examples of rapid improvement in the EIPM initiatives. It clearly indicates that, given the complex nature of healthcare and policy-making, it is hard to predict which direction EIPM might take. However, its agility and ability to adapt to rapid change to provide the needed support for policy-makers indicate that we might not reach a point where we can say that this field is doing enough because each achievement will highlight the need to do just more in a different dimension. An essential role of EIPM is to strengthen the importance of evidence in decision-making in healthcare, which is increasingly complex given the exponential growth of research and information. EIPM is only a few decades old, yet it has accomplished a lot so far. Although the main approach that EIPM advocates have used was policy brief and policy dialogue, it evolved dramatically and showed great agility and flexibility to accommodate the unpredictable world. For instance, during the COVID-19 pandemic, McMaster University constructed the COVID-19 Evidence Network to support Decision-making (COVID-END) at the start of the pandemic to cope with COVID-19 by using the best available evidence.4 Although all scientists would love to see the impact of their initiatives on the policies and decisions, claiming simple achievement of this goal will be questionable given the complexity of policy-making. It is important to remember that the effects of policies are often indirect, diffuse, and take time to appear.5 Policies cannot be presented as discrete interventions to tackle specific problems, whose effects can then be reliably measured and evaluated. It has been reported that policies are always influenced by many other factors other than evidence.6 There is a high chance that a policy will produce an effect that is not measurable and not attributable. In addition, we should keep in mind that a policy impact might be cumulative of many different initiatives. Therefore, unless the impact and influences of other interlinked initiatives are well considered, a policy’s real impact cannot be properly understood. Given this complex nature of policy-making, the weak achievement of EIPM in monitoring and evaluation should not be superficially attributed to this field. Instead, it should go deeper into the political nature of policy-making. Hence, we might realize that there is not so much a lack of recommendation for monitoring and evaluation, just a lack of realistic conceptualization. Ellen and Ben-Sheleg highlighted that EIPM scientists are failing to monitor and evaluate EIPM initiatives’ impact.7 we reported that different countries took different approaches to advocate for better utilization of evidence in the policy-making process. These approaches might be setting the priority, proof of concept, building capacity, or writing a policy brief. While looking from the outside and comparing to countries that are very advance in the EIPM field, such efforts might be tangible and not enough to reach the intended change. Yet the impact of such initiatives is reported to be dramatic in creating a case of success, clarifying the concept, and getting the buy-in from policy-makers and stakeholders.7 Therefore, the short-term wins should not be underestimated, and evaluating its role in making the change should always be tightly connected to the context where the initiative is taking place. Hence, we should ask if we need a major shock to the system to initiate change. Or can there be incremental change? In the original paper,8 more can be utilized from the implementation science to advance the EIPM field. It is anticipated that knowledge translation and implementation science can be leveraged to advance the EIPM by improving the fit between problems and approaches to implantation through a theory-driven, staged, and systematic approach that integrates knowledge translation principles and processes and involves key stakeholders’ interest.9 Ellen and Ben-Sheleg touched on the importance of utilizing the advancement in the other filed, such as behavioral economics and theory of change. While the essence of knowledge translation is connected to different social science theories , Not applicable. Author declares that she has no competing interests. SAS is the single author of the paper.


Oortwijn et al continue their guide to good practice in the use of deliberative processes in health technology assessment (HTA) based on a survey of international practice. This is useful, and I applaud their care in maintaining objectivity, especially regarding the treatment of moral and politically controversial issues, in reporting how jurisdictions have handled such matters in designing HTA procedures and in their execution. To their suggestions for future research, I add: the historical development of deliberation in healthcare decision-making and in other fields of public choice, with comparisons of methods, successes and failures; development of guidance on the design and use of deliberative processes that enhance decision-making when there is no consensus amongst the decision-makers; ways of identifying and managing context-free and context-sensitive evidence; and a review of high-level capacity building to raise awareness of HTA and the use of knowledge translation and exchange (KTE) and deliberation amongst policy makers, especially in low and middle-income countries. There is much to commend in these papers, and I have nothing to criticise in either their rapportage or their recommendations. I also applaud the careful way in which they have maintained objectivity, especially regarding the treatment of moral and politically controversial issues, in reporting how various jurisdictions have handled such matters both in the design of HTA procedures and in their execution. This distance is not seen everywhere and, indeed, the philosophical origins of deliberation in public decision-making historically build on strong normative propositions from which it is not easy to escape, and rely also on conceptual precision which is not always in evidence.5 Oortwijn, Jansen and Baltussen (henceforth OJB) continue their practical guide on promoting the use of deliberative processes in health technology assessment (HTA),6 Nor is it entirely true to say that the design and implementation of deliberative processes is in its infancy.8 It may be true that “increasingly, decision-makers are urged to organise fair, legitimate processes in health benefit package design, with legitimacy referring to the reasonableness of decisions as perceived by stakeholders,” but the urging in many jurisdictions does not come from politically influential circles (academics in particular never fail to urge), and OJB’s assertion that “evidence-informed deliberative processes were developed in response” betrays unfamiliarity with a copious philosophical literature and much practical experience with deliberative processes (evidence-based or other-based) in citizens’ juries, panels and the like.9 whose idea of rational discourse as a foundation of liberal democracy has influenced much modern analysis,10 Lindblom11 on muddling through, and less abstract specific work in non-health territories, some as distant from health policy as waste management.12 These earlier developments and applications were highly normative, and continue to have an influence that is not entirely benign. The explicit use of HTA in the design of health benefits in public insurance plans is, however, a recent phenomenon. Deliberative processes had been discussed before HTA or like methods were formalised and in contexts distant from healthcare and insurance package design, mainly concerning the meanings to be attached to central ideas like “evidence.” Major philosophical contributions were by Habermas,12 Outside the research community, colloquial evidence is anything factual that provides a reason for believing in something. In research, evidence is gathered in order to test hypotheses; evidence is empirical information that is explicit , systematic (using transparent and explicit methods for codifying), and replicable (so that using the same methods with the same samples generates the same results). Health policy-makers are more likely to use the broadly inclusive, colloquial, definition of evidence, though the evidence-based decision-making movement has engendered a greater  regard for scientific forms.14 Either way, there is a need for decision-makers to possess the competence to interrogate evidence generators, like researchers; there is a need for the evidence itself to be evaluated and interpreted; and there is a need for decisions about who should do the interrogation, evaluation and interpretation. The culture gap can be huge, as can the difference in personal and institutional interests of professional advocates for HTA and deliberation, on the one hand, and of those with decision-making authority on the other. If the latter are to “follow” science, they need first to understand it well enough to be able to interrogate the scientists. HTA operates everywhere in multi-cultures, where absence of mutual understanding and cross-communication can be huge barriers. Consider colloquial and scientific evidence.17 This requires evidence on what actually works in the “real world,” when the controls governing scientific experimental methods are relaxed, and when such evidence is combined with evidence from the context of application. Context-free guidance indicates what we understand to work in general. Context-sensitive guidance shows both what works and how (or whether) it might be usefully implemented in the specific circumstances under consideration. In either case, there is a need for processes that enable different types of scientist  to work together and, when working in specific circumstances of application, also to work with patients, carers, manufacturers, advisers, managers and decision-makers  to address issues of implementation, organization, attitudes , budgeting, modelling, forecasting, economics, ethics and others. There are two distinct views on the role of science in health system guidance. One (identified closely with evidence-based medicine) is that lab-based science and randomized controlled trials can reveal universal truths. This view provides the basis for context-free guidance. Context-sensitive guidance, on the other hand, is built on the view that evidence has little meaning or importance for decision-making unless it is adapted to the circumstances of its application. Evidence is inherently uncertain, dynamic, complex, contestable, and rarely complete. A process is required to assess its relative merits and limitations in the light of the issue at hand. The deliberative process must be able to access, combine and interpret the population of evidence of all relevant kinds, qualitative and quantitative, context-sensitive or context-free. It should not seek certainty, nor pretend to a wider audience to have found it.values, including evidence about the values held by relevant interest groups and individuals. These values might commonly include a concern for the fairness of a distribution of benefits and harms and how open to external challenge the process and its outcomes ought to be. Some may also, moreover, relate directly to the way in which decisions might impact on specific individuals, especially persons of political importance. OJB recognise this as a context-free generalisation, ie, a set of issues that all HTAs need to address, with their resolution being a matter for decision in the specific local context. Context-free guidance needs to be kept distinct from values that are context-sensitive, for example, the value-judgement that HTA ought always to promote greater equality in life-time health status, or one asserting that HTA ought not concern itself with distributional concerns over life-time health status, or that the damage done by traditional healers’ unhygienic methods is tolerable. Such value-judgements may appropriately apply in jurisdiction A but not in jurisdiction B. OJB wisely construct their Box 1 (58 questions to be addressed) as questions, whose answers will usually be context-sensitive, and therefore not answerable as though the context did not matter. Deliberative processes can do more than merely combine evidence of widely different kinds. They can also reveal and combine  consequence of a deliberative process as it is an aim to be sought. OJB state that “reimbursement decisions are ideally reached by consensus” but they also recognise that consensus cannot always be achieved. They fail to note, however, that deliberation may also reveal the reasons for lack of consensus and identify those interests of the people most involved which may facilitate the identification of a more consensual decision, or at any rate a satisfactory politically managed solution. Deliberation can also be usefully informed by sensitivity analyses designed to explore the consequences of making a variety of assumptions about the character and size of potentially context-sensitive factors. Some guidance as to how best to prevent failures to agree and the address those that nonetheless arise, would be a useful further extension of OJB’s work. The presence or absence of consensus amongst the parties to a decision is as much a One of the biggest challenges for HTA lies in the related territories of knowledge translation and exchange (KTE), and in building and maintaining the capacity of healthcare systems and the political structures, such as professional societies and public ministries, that support them. To understand HTA and its uses, to commission the work needed for HTA bodies to do their work, and to embrace HTA evidence and reasoning into top level policy decisions plainly requires deliberation.18 It is only recently that scientists have begun to learn how to share their research findings other than by publishing in peer-reviewed journals and presenting at conferences to other scientists. A pioneer in developing technologies for genuine KTE has been Toronto’s Institute for Work & Health (https://www.iwh.on.ca), specifically in the field of workplace health and safety, which is the basis for my own hands-on experience with effective KTE. A recurrent theme in much writing about progress with the institutionalisation of HTA is the lack of political understanding, or the lack of technical capacity, or both, at high regional or national levels, which is widely recognised as a major barrier to progress. The four main components of the IWH strategy are:Building relationships: formal networks with policy-makers, professional practitioners and clinicians, professional organizations, etc. Building engagement into research: involving knowledge users and other stakeholders in specific research projects beginning early in the research process, whereby stakeholders can provide guidance in shaping the research question and give information about the context in which research results are likely to be used. It continues to the end of the research project, when stakeholders help craft research messages in ways that are meaningful to the intended audience. Enhancing capacity: helping external audiences understand and apply research through Systematic Review Workshops, research presentations at which stakeholders can directly learn from, and ask questions of, scientists. Communicating finding: creating a communications strategy directed at stakeholders. Communication tools might include a central website, newsletters, monthly e-bulletin, plain-language summaries, videos, coverage in general and trade media, and social media . exchange rather than a unidirectional flow of information from researchers to users). It would be a valuable extension of OJB’s work, to review this and other working experience of KTE . Most of the world’s populations served by healthcare do not live in democracies, and many jurisdictions do not share a value that exposes decision-makers to critical examination. The prime purpose of some healthcare systems is to make profits. Others seek to maximise human productivity. These features vary contextually and, if HTA is to be a universally helpful tool, it is wrong to require a specific context to form its only proper application. Many believe, as I and OJB do, that a rational consensus developed through discussion is a useful normative guide in liberal democratic policy making. HTA enhances democracy and democratic processes. The same has been claimed of deliberation since Habermas. There is no reason, however, why deliberation may not enhance decision-making in single party states and theocracies or, indeed, even in charitable or for-profit healthcare insurance and delivery systems owned and operated by clinicians, limited liability companies or even traditional healers. It should be a context-free condition that HTA is always and everywhere a  OJB suggest two main themes for future work in this field. The first is to document more completely the ways in which legitimacy is addressed and decision criteria are chosen; the other is to assess effective impact of using deliberation to design HTA procedures and health benefit packages. I support both proposals and would add a further five:The preparation of an account of the historical development of deliberation in healthcare decision-making and in other fields of public choice, with qualitative and quantitative comparisons of methods, successes and failures. Further exploration of how best to identify and then manage context-free and context-sensitive evidence (and the design of frameworks for deliberative thinking about them). Development of guidance on the design and use of deliberative processes that enhance decision-making when there is no consensus amongst the decision-makers. Effective methods of ensuring, when representation is a desideratum, that the usual diversity of social values, to be found in all populations, is appropriately embodied in deliberative groups. A major review of high-level capacity building, especially in low and middle-income countries, covering mechanisms such as KTE, and with assessments of (cost-) effectiveness and markers of likely success.  Not applicable. Author declares that he has no competing interests. AJC is the single author of the paper.