This narrative review analyses the Australian Guideline (2018) for the treatment of knee osteoarthritis (KOA) developed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The Guideline recommended against the use low-level laser therapy (LLLT). Why this conclusion was reached is discussed in this review in the context of evidence provided in other systematic reviews, the latest of which was published in 2019 and which provided strong support for LLLT for knee OA. We evaluated the reference list cited for the recommendation “against” LLLT and compared this with reference lists of systematic reviews and studies published before and after the publication date of the Guideline. Eight randomised controlled trials (RCTs) of LLLT were cited in the Guideline the latest of which was published in 2012. There were seventeen additional RCTs, five of which together with one systematic review were located in the year of publication, 2018. The most recent systematic review in 2019 included 22 RCTs in its analysis. Discordance with the levels of evidence and recommendations was identified. Although GRADE methodology is said to be robust for systematically evaluating evidence and developing recommendations, many studies were not identified in the Guideline. In contrast, the latest systematic review and meta-analysis provides robust evidence for supporting the use of LLLT in knee OA. The conflict between guidelines based on opinion and evidence based on meta-analysis is highlighted. Given the totality of the evidence, we recommend that the Australian Guideline should be updated immediately to reflect a “for” recommendation. Clinical practice guidelines are used by health professionals to promote evidence-based practice, but controversies exist regarding transparency of recommendations, possible bias and how to keep guidelines current when new information becomes available. GRADE  methodology which is described as a “a transparent framework for developing and presenting summaries of evidence and provides a systematic approach for making clinical practice recommendations” has been developed to address such areas of concern . The GRAIn 2018, the Royal Australian College of General Practitioners (RACGP) published a Guideline for the management of knee and hip osteoarthritis (OA) (referred to as “the Guideline” herein) . For kneFirstly, we outline the GRADE procedures used by the Working Group to arrive at the “conditional against” recommendation for the use of LLLT in knee OA .The first step in the GRADE process is to identify studies on which GRADE quality of evidence assessment is based. The methods used by the Working Group followed accepted principles. The PICO  questions developed by the Working Group were similar for all of the interventions investigated. For LLLT, the PICO question sought to identify “benefits and harms of laser in the management of patients with knee OA” (p. 67). Importantly, search terms such as “laser therapy”, “photobiomodulation” and “LLLT” did not appear in the search strategy .To confirm that all available RCTs were identified within the time frame prior to the Guideline publication, we conducted a search of all published systematic reviews of LLLT in knee osteoarthritis (KOA) to 2019, hand-searched the reference list in each review and conducted an additional search of LLLT literature to identify any additional RCTs.The next step undertaken by the Working Group was a quality assessment of the eight identified studies and formulation of the evidence report incorporating the GRADE evidence profiles categorised as high, moderate, low and very low. The Working Group did not perform any meta-analyses and no list of excluded studies was supplied. For LLLT, the evidence was rated by the Working Group as “low” though the Guideline stated that there are “clinically meaningful benefits in short-term pain and function (up to three weeks)” (p. 38). Considering this positive statement, we proceeded to a more detailed analysis of the recommendations.A final step in the GRADE process is the formulation of recommendations designated as (i) “strong recommendation ‘for’”, (ii) “conditional recommendation ‘for’”, (iii) “neutral”, (iv) “conditional recommendation ‘against’” and (v) “strong recommendation ‘against’”. The recommendations are based not only on the quality of the evidence but also on subjective assessments of the balance between benefits and harms, values and preferences as perceived by the Working Group, and resources for the options under consideration. We compared the evidence and rationale for the GRADE recommendations for a random sample of other non-pharmacological and pharmacological treatment options in the Guideline.Eight RCTs for LLLT were cited in the Guideline –12, the To date, we have located a total of twenty-five studies of LLLT for KOA or knee pain, seventeen of which were not cited in the Guideline though were available up to 2018 –35. One Of these, there were seven double-blind randomised studies comparing LLLT with placebo (sham laser) –24, 35. p < 0.001) [p < 0.05) [p = 0.003) [p < 0.05) [p < 0.001) [Since the Guideline was published, several additional studies which further extend the evidence base regarding LLLT and KOA were identified: a double-blind RCT of LLLT + exercise compared with sham LLLT versus exercise at 3 and 6 months after a course of 10 treatments and showed a significant decrease in analgesic rescue medication in the laser group at 6 months after treatment (< 0.001) ; a doubl < 0.05) ; a singl= 0.003) ; a singl < 0.05) ; a doubl< 0.001) ; and a s< 0.001) .n = 1063) and found strong evidence for the reduction in pain and disability with LLLT for KOA with no adverse effects [Since the publication of the Guideline, a systematic review and meta-analysis included 22 RCTs . It is unclear why this should be a judgement against LLLT treatment given that most physical therapies including exercise and massage are rarely delivered in a single treatment. From the perspective of time burden, the duration of LLLT treatment would generally be from 20 to 30 min as a maximum. Importantly, the therapeutic benefits of LLLT are based on modulating the underlying pathology and are multifaceted encompassing tissue repair, modulation of inflammation and neural blockade, which are cumulative over several treatments. In contrast, many of the recommended treatments in the Guideline are for symptom management only lasting hours (such as Paracetamol or NSAIDs), or a few weeks at best (such as corticosteroid injection). Massage which also requires repeated treatments is recommended with the same “low” level of evidence as LLLT but is recommended on the basis that it can facilitate more active treatment. If the latter is a reason for inclusion in the Guideline, then the evidence for LLLT is substantial, as several of the studies not included in the Guideline compared LLLT with and without exercise and the majority found that exercise capacity and hence, function is enhanced when combined with LLLT. Moreover, recommended treatments of exercise, dietary advice and psychological support also require considerable time and expenditure.From a cost perspective, many health professionals  can administer LLLT as monotherapy or as an adjunct to other therapies. Cost versus benefit is especially relevant when balancing benefits versus harms in the relatively urgent search to find non-opioid alternatives for painful conditions. As LLLT was adjudged to be effective, the resources and costs of LLLT may prove to be less than the long-term burden and costs of drug-taking, especially of opioids or NSAIDs. How much patients value the importance of a treatment may be reflected in their willingness to pay for such treatments. An example cited by Zhang et al. is patients with chronic obstructive pulmonary disease who are willing to pay $13.46 to avoid mild side effects and $67.51 to gain symptom relief . More imAnother of the reasons not to recommend LLLT was said to be the lack of follow-up beyond 3 weeks in the cited studies. This was factually incorrect as at least one of the studies located by the Working Group had a follow-up period of 8 weeks . AlthougA fourth issue with the Guideline is the lack of expert input during the development of the recommendations. Balshem and colleagues make the important observation that, “Developing recommendations always requires the opinion of experts….” . To our Given the rapidity of technological developments and an exponentially increasing number of publications, our review demonstrates that guidelines can become outdated as soon as they are published without an appropriate mechanism to make any guideline a “living” document. Updating of guidelines appears to be an ad hoc process with an international survey finding that only 53% of guideline developers had in place a formal procedure for deciding when a guideline is out of date . Given tIn a broader context, given the limitations of available treatments and the current imperative to offer non-drug treatments without serious side effects, the conditional “against” recommendation is difficult to understand Table .GRADE methodology is generally robust; however, for the process to be effective, a basic tenet is that all the evidence should be reviewed. We believe that the Guideline does not reflect the current evidence for LLLT for knee OA. In contrast, the latest review and meta-analysis  stronglyGiven the factors we have identified, we believe that the Guideline should be reviewed immediately and changed from a “conditional against” recommendation for the use of LLLT in KOA to a “for” recommendation to reflect the strength and totality of the published LLLT literature Fig. .Fig. 1Co


Latency establishment is the hallmark feature of herpesviruses, a group of viruses, of which nine are known to infect humans. They have co-evolved alongside their hosts, and mastered manipulation of cellular pathways and tweaking various processes to their advantage. As a result, they are very well adapted to persistence. The members of the three subfamilies belonging to the family Herpesviridae differ with regard to cell tropism, target cells for the latent reservoir, and characteristics of the infection. The mechanisms governing the latent state also seem quite different. Our knowledge about latency is most complete for the gammaherpesviruses due to previously missing adequate latency models for the alpha and beta-herpesviruses. Nevertheless, with advances in cell biology and the availability of appropriate cell-culture and animal models, the common features of the latency in the different subfamilies began to emerge. Three criteria have been set forth to define latency and differentiate it from persistent or abortive infection: 1) persistence of the viral genome, 2) limited viral gene expression with no viral particle production, and 3) the ability to reactivate to a lytic cycle. This review discusses these criteria for each of the subfamilies and highlights the common strategies adopted by herpesviruses to establish latency. Herpesviruses are a family of enveloped viruses with large double-stranded DNA genomes . Their lHerpesviruses include three subfamilies: Alpha-, Beta-, and Gammaherpesvirinae, each one of them having different characteristics with regard to tropism, length of the replicative cycle and associated diseases. The Alphaherpesvirinae, including HSV-1 and 2 and VZV, show relatively broad host and cell tropism infecting both human and non-human cells. With regard to the cell types, in vitro virtually all types can become infected including fibroblasts, epithelial cells, and neurons . The repAs mentioned earlier, herpesviruses have large dsDNA genomes that are linear when inside of the viral particle, however they become circularized upon entering the infected cell . During Herpesviral genomes inside the viral particle are compacted with the help of spermine, but do not contain nucleosomes ,30,31. IThe original definition of latent and lytic states in case of herpesviruses describes the lytic cycle as the phase in which transcription from the viral genomes is very high, all or almost all the viral genes are expressed, and latency as a condition when only a limited number of genes is expressed. However, the more sensitive assays we use and the more we know about the latent expression the less limited it appears to be. The subfamily of herpesviruses that is most studied with respect to latency are the gammaherpesviruses; therefore, we will start the overview of the latent programs from them.EBV infects naïve B cells, which are the most abundant cells circulating in the blood, and uses B cell differentiation to promote viral latency establishment in the long-lived memory B cells . StudiesThe functions of the EBV latent proteins allow the virus to successfully persist in the infected cells. EBNA-LP and EBNA-2 are responsible for the transcriptional regulation of expression of other latency proteins . EBNA1 pIn addition to protein expression, also non-coding RNAs are expressed in all types of EBV latency, these include EBV-encoded small RNAs (EBER 1 and EBER2), miRNAs encoded in the BamHI A rightward transcript (BART) and the BHRF1 locus as well as recently identified circular RNAs ,47,48,49The second human gammaherpesvirus, KSHV, so far is not known to have multiple latency programs, the way it has been described for EBV. Instead, there are four major open reading frames (ORFs) expressed during KSHV latency: ORF73 (LANA), ORF72 , ORF71 , and ORF K12 (Kaposins)  27]. LA. LA27]. In addition to the four major latent KSHV ORFs expressed in the KSHV-associated tumors: PEL (primary effusion lymphoma) and KS (Kaposi’s sarcoma) cells, there is also vIRF3 , which is expressed only in PEL and multicentric Castleman’s disease (MCD) . This prSimilar to EBV, KSHV also encodes non-coding RNAs, including miRNAs ,86, longInitially, the latency program for HCMV was thought to include, as in the case of other herpesviruses, a limited number of genes. Therefore, also in the case of this virus several genes associated with latency were identified, including: UL138, UL111A, latency unique nuclear antigen (LUNA), US28, a splice variant of IE1—IE1x4, lncRNA2.7, 4.9, and UL144. UL138 is required for HCMV latency establishment  28,93],,93], it Some of the HCMV proteins show expression of specific splice variants depending on the phase of the viral life cycle. One such example is UL111A, which encodes a viral homolog of IL-10, which is expressed in the lytic cycle, while in latency a shorter splice variant LAcmvIL-10 is detected ,107. CelAll of the HCMV transcripts described above play undoubtedly crucial roles in latency, however, an increasing number of studies show that the expression pattern in latency includes many more genes ,114,115.Most of the human herpesviruses maintain their genomes during latency in an extrachromosomal form of episomes. However, as mentioned earlier, HHV-6A/B represents a unique example of genome integration into telomeric regions of chromosomes . Since HThe transcriptional activity of integrated HHV-6A/B genome has not been studied extensively. In fact, comprehensive annotation of HHV-6A and HHV-6B genomes has been carried out only very recently . Long beUnfortunately, mechanisms of HHV-7 latency establishment and maintenance are still under investigation and latency genes of HHV-7 have not yet been identified.Initially, HSV latent transcription was considered to be limited to the latency associated transcripts (LATs), which are found on the opposite strand of the ICP0 locus, encoding the major immediate early protein  129,130130. Of nIn VZV-latently infected human ganglia, several transcripts have been detected including ORF21, 29, 62, 63, and 66 ,171. FurHerpesviruses from all the three subfamilies can periodically reactivate to cause symptomatic recurrent infection or be asymptomatically shed to new hosts. Reactivation and re-entering a lytic cycle can be triggered by a broad range of physiological and environmental factors . Plasmodium falciparum, Leptospirosis, and Group A Streptococci stimulate EBV reactivation .,212.8,21Although the most significant site of HCMV persistence is the myeloid lineage, HCMV can also establish latency in other cell types. There are studies confirming HCMV latency establishment in neural lineage, particularly in primitive neural stem cells, therefore suggesting a link to pathology of central nervous system observed in children with congenital CMV disease . SimilarIn cultured latently infected peripheral blood monocytes (PBMs), the differentiation-dependent shift of HCMV to the lytic cycle can be induced by granulocyte colony stimulating factor (G-CSF) and hydrocortisone. Although the above mentioned substances were observed to induce the expression of viral immediate early (IE) and early (E) genes, the production of infectious virus was not detected . HoweverHHV-6A, HHV-6B, and HHV-7 that belong to the Roseolovirus genus of betaherpesviruses share common mechanisms of establishing latency and reactivation. Similar to HCMV, HHV-6 also establishes latency in CD34+ hematopoietic stem cells  and in mAmong the Roseolovirus genus, latent HHV-6B and HHV-7 present in cultured cells can be reactivated by TPA ,235, whiThe frequency of clinical reactivation varies among alphaherpesviruses. Symptomatic reactivation of HSV may occur repeatedly and mostly in young people, whereas clinical reactivation of VZV typically occurs once in a lifetime and mostly affects elderly people . The reaUnder experimental conditions, several molecular pathways have been targeted to reactivate alphaherpesviruses. Continuous nerve growth factor (NGF) signaling has been known to be essential for maintaining HSV latency in neuron model systems of mice and rats. Thus, withdrawal of NGF from latently infected cultures leads to reactivation of the lytic cycle ,253. InhHost genetic variation, which is a component of infectious disease pathogenesis, has also been found to be associated with frequency of reactivation of herpesviruses. It was suggested that impaired surveillance of latent KSHV infection in individuals from Africa might be associated with 2 HLA-A alleles, A*6801 and A*4301, and 1 HLA-DRB1 allele group, DRB1*04, resulting in enhanced KSHV shedding in saliva . MoreoveGreater focus on host genetics of herpesviral infection is needed to predict which individuals are at higher risk of viral reactivation and complications caused by recurrent infection. In the future, larger genomic studies can bring breakthroughs in understanding the host response to herpesviruses.On the organism level, it is thought that the reactivation of herpesviruses is a combination of both immunosuppression and factors that act directly on latently infected cells. On the cellular level, virus reactivation is believed to be the result of a disturbed ‘balance’ between signaling pathways that activate and inhibit viral lytic replication. Generally, harsh conditions can lead to virus reactivation and progeny production in order to be spread to new hosts. Although certain environmental stimuli are well defined, our knowledge of the exact mechanisms and conditions leading to lytic switch is incomplete. However, the regulation of the latency to lytic switch is essential to develop novel therapeutic strategies that could target the latent human herpesviruses.Different herpesviruses establish latency in different cells, which affects the characteristics of the process. The common feature for all herpesviruses is the persistence of the genome in form of an episome, the difference with regards to persistence lies in that the beta- and gammaherpesviruses, encode a protein participating in latent replication and genome tethering, and alphaherpesviruses, do not have such a protein, as they persist in non-dividing neurons. Genomes of all herpesviruses become chromatinized upon entering the cell, therefore transcriptional activity of all of them is subject to regulation by chromatin modifications. With regard to gene expression in latency, at first glance each subfamily seems to have its own distinctive pattern . AlphaheHerpesviruses have the ability to reactivate from latency to lytic cycle. Immunosuppression—due to i.e., exposure to UV radiation, stress, or chemotherapy—is a common inducer of the lytic cycle of all herpesviruses. The presence of proinflammatory cytokines is another signal that tends to reactivate herpesviruses. In the case of HCMV the reactivation is observed during the process of myeloid differentiation, which is associated with cytokine secretion. The final differentiation step of memory B cells to plasma cells is also a signal for EBV to enter the lytic cycle. Hypoxia is an important stimulus inducing the lytic cycle in Alphaherpesvirinae (HSV-1) and Gammaherpesvirinae . Finally, infection with another pathogen can also induce reactivation of the latent beta- (HHV-6B) or gammaherpesviruses .Even though latency looks a bit different in case of each of the subfamilies of the Herpesviridae with increasing number and sophistication of the model systems as well as improved sensitivity of assays the common features of the hallmark of herpesviruses—their latency state—start to emerge .


People with severe mental disorders (SMD) experience premature mortality mostly from preventable physical causes. The World Health Organization (WHO) have recently produced guidelines on the management of physical health conditions in SMD. This paper presents the evidence which led to the recommendations for tobacco cessation and management of substance use disorders in SMD.Scoping reviews informed 2 PICO  questions relating to tobacco cessation and management of substance use disorders in SMD. Systematic searches led to the identification of systematic reviews with relevant evidence to address these questions. Retrieved evidence was assessed using GRADE methodology, informing the development of guidelines.One thousand four hundred thirty-four records were identified through systematic searches for SMD and tobacco cessation, of which 4 reviews were included in GRADE tables and 18 reviews in narrative synthesis. For SMD and substance use disorders, 4268 records were identified, of which 4 studies from reviews were included in GRADE tables and 16 studies in narrative synthesis.People with SMD who use tobacco should be offered combined pharmacological  and non-pharmacological interventions such as tailored directive and supportive behavioural interventions. For people with SMD and substance use disorders , interventions should be considered in accordance with WHO mhGAP guidelines. Prescribers should note potential drug-drug interactions. Recommendation were conditional and based on low/very low certainty of evidence with a scarcity of evidence from low- and middle-income settings.These guidelines mark an important step towards addressing premature mortality in people with SMD. The dearth of high-quality evidence and evidence from LMIC settings must inform the future research agenda.https://www.who.int/mental_health/evidence/guidelines_physical_health_and_severe_mental_disorders/enGuidelines: https://www.who.int/publications-detail/mhgap-intervention-guide%2D%2D-version-2.0 The severe mental disorders (SMD), defined as schizophrenia-spectrum, psychoses and bipolar disorders as well as moderate to severe depression, are associated with markedly reduced life expectancy . WorldwiAlthough deaths from suicide and other unnatural causes may be more likely in this group compared to general populations, the majority of deaths are in fact due to preventable physical causes, such as cardiovascular disease, respiratory disorders, cancers and infectious disease . In addiA history of substance abuse in populations with SMD has been shown to be associated with an increased risk of death from all-causes and from unnatural causes –16. In aManagement of physical health conditions in adults with severe mental disorders”  format. The research questions guided which physical health conditions and risk factors were to be addressed in the final disseminated guidelines . This prFigure Timelines- Published within the last 5 years, preferably within the last 3 years; (2) Quality- Papers included for GRADE assessment had sufficiently high methodological quality ratings on the ‘Assessment of Multiple Systematic Reviews’ tool (AMSTAR) [Relevance- Retrieved papers were closely relevant to the PICO population. However, where relevant evidence could not be identified these criteria were relaxed, leading to ‘indirect evidence’ to inform recommendations  (AMSTAR) –28 (see  (AMSTAR)In order to inform the development of evidence based guidelines in a transparent manner, the GRADE approach was used . An advaPrior to selection for GRADE assessment, retrieved articles had to meet sufficiently high quality ratings on the AMSTAR tool –28. The GRADE evidence profiles for each of the PICOs were presented and discussed over a series of roundtable meetings convened at the WHO in Geneva in May 2018. GDG members were selected internationally across UN member states for their expertise within the topic areas. In addition, the meetings were also attended by a guideline methodologist, the evidence review team and the WHO secretariat. The final recommendations resulted from a consideration of the background evidence for each of the PICO questions, summarised as GRADE profiles and the certainty of evidence for these, as well as taking into consideration other aspects such as whether the problem was considered a priority, how substantial desirable and undesirable anticipated effects were, whether the balance between desirable/undesirable effects favoured the intervention over the comparator, the value attached to the outcomes and the certainty of evidence relating to likely resource requirements, cost effectiveness, impact on health equity, acceptability and feasibility of the intervention. In addition the acceptability of the intervention to healthcare providers in LMICs, feasibility of the intervention and the impact of the intervention on equity and human rights were considered.For people with SMD who use tobacco, are pharmacological  and/or non-pharmacological interventions effective to support tobacco cessation?For people with SMD and substance  use disorder, are pharmacological and/or non-pharmacological interventions for substance use disorder effective to support reduction in substance use-related outcomes?After consultation with the GDG and WHO GRC agreed research questions specific to tobacco cessation and substance use disorders were:In total 1434 records were initially identified through the systematic searches for SMD and tobacco cessation; after screening for eligibility and removal of duplicates, 4 reviews were included in the GRADE tables for this PICO with 18 reviews in total contributing evidence through narrative synthesis. For SMD and substance use disorders, a total of 4268 records were identified. After screening and checking against eligibility criteria, 4 studies were included in the GRADE tables on this topic with a total of 16 studies included in the narrative synthesis. Figures https://www.who.int/mental_health/evidence/guidelines_physical_health_and_severe_mental_disorders/en/). The GDG recommended combination pharmacological with behavioural interventions, as behavioural interventions alone have been shown to result in a relatively low abstinence rate for tobacco use in SMD.For tobacco use in SMD, GRADE evidence profiles were compiled for: the use of Buproprion, Varenicline and Nicotine Replacement Therapies (NRT) . In addition, GRADE profiles for non-pharmacological interventions ), supplementing NRT were compared to standard care approaches, and the use of contingent reinforcement (using money/money plus NRT) compared to care-as-usual was assessed with GRADE –33 .Pharmacological interventions identified for tobacco cessation in SMD populations were: NRT, Bupropion and Varenicline. Evidence for the efficacy of these interventions in SMD populations mostly derived from high income settings with a few exceptions (e.g. studies for Bupropion which had been conducted in China and Iran as well as in the USA). These pharmacological interventions for tobacco cessation are already recommended by the WHO in general populations, although only NRT is on the WHO essential medicines list . SearcheFor substance use disorders and severe mental disorders, assessment of evidence using the GRADE approach included a review of evidence relating to psychological interventions such as CBT plus motivation interviewing (MI) versus care-as-usual, CBT versus care-as-usual, MI versus care-as-usual and contingency management versus care-as-usual for people with SMD and substance use disorders . Brief iAll of the main recommendations relating to each of the PICO questions are presented in Table https://apps.who.int/iris/bitstream/handle/10665/275718/9789241550383-eng.pdf?ua=1).In general, the assessment of evidence using GRADE methods indicated low to very low certainty evidence from randomised controlled trials of pharmacological interventions for the management of mental disorders (whether through the use of antipsychotics or antidepressants), which did not indicate the superiority of any of the surveyed medications, when prescribed for people with SMD comorbid with substance use disorders –38. ModeFor both comorbid tobacco use and substance use disorders, where retrieved evidence was of very low certainty, the expertise of the international GDG was sought, who applied their expertise to the topic area. As a result of the low/very low certainty of evidence retrieved, resultant recommendations were conditional. A ‘conditional’ recommendation by the GDG indicates that GDG members concluded that beneficial effects of the intervention probably outweighed undesirable effects but with insufficient evidence for the GDG to support a ‘strong’ recommendation . For people with SMD and substance  use disorder, the low certainty of evidence led to the recommendation that the mhGAP guidelines for the management of substance use disorders should be followed Table .The full GRADE evidence profiles are displayed in the supplementary materials  may be restricted in certain contexts, although other interventions (such as NRT) are more widely available. Other factors relating to acceptability of the guidelines and longer term sustainability across countries will need to be monitored. Future guidelines may reflect feedback from people on the ground at the forefront of implementing these guidelines on tobacco use and substance use disorders in SMDs- for example following feedback from health care practitioners, policy makers and public health practitioners.Tobacco use and substance use disorders play an important role in heightening the risk of premature mortality in people with SMDs. Our search of the evidence highlighted gaps in the evidence base, which may in part be due to the systematic exclusion of people with SMDs from clinical trials. Despite the challenges described in this paper, these guidelines may mark an important step towards addressing premature mortality in people with SMD. The recommendations may help to inform policy and decision makers globally and in LMIC settings in ensuring more equitable access to tobacco cessation and substance use disorder services for these populations. However the dearth of high-quality evidence and evidence from LMIC settings must inform the future research agenda.Additional file 1: Table S1. Search terms. Search terms for each PICO question.Additional file 2: Table S2. Additional search strategies used to identify relevant drug-drug interactions. Search terms specific to potential drug-drug interactions identified in each PICO question.Additional file 3: Table S3. Overview of systematic review searches. Overview of search strategies detailing number of reviews identified.Additional file 4. PRISMA 2009 Checklist


An evidence-based practice (EBP) team at an academic medical center supports the development of evidence-based hospital policies and protocols via “Evidence Briefs.” An early career librarian was added to the EBP team to meet increased requests for Evidence Briefs, which provided an opportunity to initiate a quality improvement (QI) analysis, improve work flow, and cross-train staff on literature searching and article selection skills.This QI project evaluated literature searching and article selection skills of an early career librarian (less than 2 years' experience), a mid-career librarian (more than 10 years' experience), and a critical appraisal expert. This project examined 10 Evidence Brief requests completed within a 6-month period. Analysis of each individual's performance of literature searching and article selection was completed for each Evidence Brief. Across all Evidence Brief requests, the mid-career librarian performed the most comprehensive literature searches and captured the highest number of articles that ultimately ended up being included in Evidence Briefs (75%). The critical appraisal expert performed best on the article selection portion of the project and identified the highest number of relevant articles that were included in Evidence Briefs (74%).This project provided a formalized method of assessing the literature searching and article selection skills of each member of the EBP team. This project illustrated the skill level of each individual and led to improvements in the Evidence Brief request work flow. At the authors' academic health system, the Value Institute collaborates with care teams by providing data, evidence, and tools to improve health care value. The Value Institute, which resides in the hospital's Quality Department, provides quality analytics and evidence-based practice (EBP) support to create a culture of data-driven and evidence-based decision making. One way the Value Institute supports clinical inquiry and integration of EBP at the bedside is through developing clinical decision support (CDS) tools. CDS tools aim to improve quality of care through the Five Rights model: communicating the right information to the right stakeholder, at the right point in the work flow, through the right channel, and the right format . The ValThe Value Institute's EBP team supports the development of evidence-based hospital policies and protocols via “Evidence Briefs.” Evidence Briefs include a narrative summary and a table of best evidence for a single clinical question to assist with clinical decision making; however, they do not directly offer practice recommendations. Evidence Briefs are developed using comprehensive literature search methods and thorough critical appraisal of best evidence in an attempt to provide an objective summary of research in a clear and useful manner . A samplFrontline staff must specify the following items during the Evidence Brief request process:Relationship of request to clinical or administrative policy updateProblem or situation in need of investigationRelationship of problem of interest to unit or hospital goalsExplanation of current processPatient/population/problem, intervention, comparison, outcome (PICO) elementsOne member of the EBP team, the critical appraisal expert, triages requests on a first-come, first-served basis and seeks clarification from the requestor before transferring the request to the medical librarian for literature review. Once the medical librarian completes the literature search and identifies pertinent articles for the clinical question, the search strategy and selected articles are emailed to the critical appraisal expert. Then, an Evidence Brief is created by critically appraising relevant articles, and the results are provided to the requestors for discussion with key stakeholders. While the “question and answer plus critical appraisal” model  is not uAt the inception of the Evidence Brief service, the EBP team comprised the mid-career librarian and the critical appraisal expert. The inclusion of a librarian on the EBP team ensured that search strategies were structured to retrieve as many relevant studies as possible, which would ultimately result in a lower risk of bias in the overall body of literature used to make decisions . The criThe volume of Evidence Brief requests grew more than 300% from 8 requests in 2014 to 35 in 2018, due to increased collaboration with nursing Shared Governance  and word-of-mouth testimony from satisfied requestors. The process established in 2014 underwent very few modifications as the program grew, except for the development of an online request form. Increased utilization of this service has improved patient care across the clinical enterprise; however, it has also placed a strain on the bandwidth of the small EBP team. To increase the program's ability to complete additional incoming requests in a timely manner, the early career librarian was added to the team in 2018.Prior to the addition of the early career librarian, there had been no evaluation of the literature searching and article selection components of the Evidence Brief process. The addition of a new librarian provided an opportunity to initiate a quality improvement (QI) analysis, improve work flow, and cross-train staff on literature searching and article selection skills.A QI project was initiated to evaluate literature searching and article selection skills of the early career librarian, who had less than two years' experience; the mid-career librarian, who had more than ten years' experience; and the critical appraisal expert. This project examined ten Evidence Brief requests that were completed within a six-month period. For every Evidence Brief request, the early career librarian, mid-career librarian, and the critical appraisal expert developed individual search strategies. Then, each person selected what they considered to be the most relevant articles to answer the clinical question. These articles were combined into one RefWorks folder and de-duplicated. The critical appraisal expert reviewed the RefWorks folder and determined—based on study design, direct applicability, and actionability—which articles to include in the Evidence Brief.Each EBP team member developed search strategies for the ten Evidence Brief requests. The number of databases that were searched and complexity of the search strategies varied depending on the clinical question. Search strategies incorporated a combination of subject headings  and keywords for each concept in the clinical question.PubMed was typically searched first, and that search strategy was modified for the other databases by replacing MeSH terms with appropriate subject headings (when available) and maintaining similar keywords. Supplemental databases that were routinely searched included Scopus, CINAHL Complete, PsycINFO, and Cochrane Database of Systematic Reviews. Resources that were less commonly searched included ECRI Guidelines Trust, ProQuest Health Management Database, TRIP Database, Google Scholar, and Google, among others. Filters such as publication date, study design, and ages were applied, depending on the clinical question and extent of relevant literature. To identify additional articles, the reference lists of relevant articles were hand searched, as well as citing articles.After the literature search for each clinical question was completed, each EBP team member recorded in a Microsoft Excel spreadsheet their respective search strategy for each database searched, as well as any filters that they applied.Each person exported all retrieved citations from their final search strategies for each database and any citations discovered through hand searching into the individual's “search results” RefWorks folder and Microsoft Excel spreadsheet. A flowchart of the process for the QI project can be found in After completing the literature searching process, each person then selected what they considered to be the most relevant articles to answer the clinical question. Article relevance was based on a variety of considerations, such as direct applicability to the PICO elements in the clinical question, as well as study design, publication date, and actionability .Each person exported the citations that they considered to be the most relevant into their “article selection” RefWorks folder and Microsoft Excel spreadsheet. The articles included in each person's “article selection” folder were then combined into one RefWorks folder and de-duplicated.The critical appraisal expert reviewed the combined RefWorks folder and determined—based on study design, direct applicability, and actionability—which articles to include in the Evidence Brief. The articles selected by each individual as most relevant were assessed to determine the proportion included in the Evidence Brief. As the critical appraisal expert selected articles for inclusion in the Evidence Brief, she documented the reasons why certain articles were not included. Examples of reasons for exclusion were protocol only, not primary literature, not head-to-head comparison, included in systematic review, and inappropriate study design.References included in each Evidence Brief were analyzed for inclusion on the spreadsheets containing all search results and selected article citations for each individual. Numbers of citations that were captured in literature searches and of articles selected by each individual were recorded in a spreadsheet where percentages were generated for comparison.Analysis of each EBP team member's performance of literature searching and article selection was completed for each Evidence Brief. For each individual, the percentage of references captured per search strategy and percentage of articles selected for inclusion in each Evidence Brief were calculated.Across all Evidence Brief requests, the mid-career librarian performed the most comprehensive literature searches and captured the highest number of articles that ultimately ended up being included in the Evidence Briefs (75%), followed by the critical appraisal expert (73%) and then the early career librarian (60%). Analysis of each individual's performance on the literature searching component for each Evidence Brief request can be found in Results of both librarians' literature searches were combined and compared to those of the critical appraisal expert to examine results of librarian-combined to nonlibrarian-developed literature searches. When combined, the search strategies of both librarians retrieved an average of 88% of articles that were selected to be included in the Evidence Briefs, compared to 73% retrieved by the critical appraisal expert. Results of librarian-combined to nonlibrarian-developed search strategies can be found in Across all Evidence Brief requests, the critical appraisal expert performed best on the article selection portion of the project and identified the highest number of relevant articles that were included in Evidence Briefs (74%), followed by the mid-career librarian (62%) and then the early career librarian (48%). Analysis of each individual's performance on the article selection component for each Evidence Brief request can be found in This project provided a formalized method of assessing the literature searching and article selection skills of each member of the Value Institute's EBP team. This is particularly important because the quality of Evidence Briefs that are provided to clinicians solely depends on the evidence that is located and selected for inclusion. While this project focused on Evidence Briefs, librarians are routinely involved in developing hospital guidelines, systematic reviews, and other projects where quality is highly dependent upon expert searching and article selection skills.This study appears to be the first published evaluation of literature searching and article selection skills of an EBP team. Although previous studies examined the impact of including librarians on clinical teams , 8, thosThis project illustrated the skill levels of each individual and led to improvements in the Evidence Brief request work flow. The new work flow allows each EPB team member to focus on their individual strengths, improves quality, and increases productivity through the time saved. A comparison of the work flow before and after the QI project can be found in The results indicate that the combined librarians' searches are equally or more effective than the searches of any individual. Going forward, the librarians have worked together to develop search strategies as opposed to one individual completing search strategies. This ensures that a comprehensive search strategy is developed and provides an opportunity for mentorship. After the QI project, the early career librarian develops the initial search, which is then tested and modified as appropriate by the mid-career librarian. Only modifying literature searches, instead of having to start from the beginning, saves time for the mid-career librarian. The early career librarian spends more time conducting the literature searches, as she develops the initial strategy for each request, and this increased exposure and practice allows her to continue developing her clinical searching skills.The librarians have implemented a formal mentoring program, where after each search is finalized, both librarians meet and discuss the search and any modifications that have been made. Both librarians are learning from each other through this experience. For example, the mid-career librarian is more familiar with terminology used in the literature to express certain concepts, and the early career librarian has been able to add those terms based on feedback. The early career librarian is also the liaison to the affiliated College of Pharmacy and is more knowledgeable when searching for requests that involve medications. Thus, she has been able to share knowledge specific to searching for drug information with the mid-career librarian. Since the results of the project show the librarian-developed search strategies were most effective, the critical appraisal expert no longer runs preliminary searches, saving her time as well.The results demonstrate that the critical appraisal expert is best at article selection. Therefore, the librarians are no longer spending time identifying articles that they believe are relevant for inclusion in Evidence Briefs. The critical appraisal expert began documenting exclusion criteria during the article selection phase, which resulted in more transparency for the team and the requestors. Thus, the documentation of exclusion criteria is now consistent practice.Additionally, new project management methods were introduced and ultimately adopted for Evidence Brief requests. Prior to this project, requests were manually tracked by the critical appraisal expert, and all communication was conducted via email. The librarians, who previously utilized the Springshare LibAnswers platform to answer patron requests via tickets and to record reference statistics, suggested using the platform for Evidence Brief requests as a project management tool. Doing so allows requests to be tracked in a central location, and ownership can be assigned and transferred seamlessly, increasing the clarity of team members' responsibilities during each phase of the process. This system also has internal notes and statistics-tracking features that enhance project management of the requests. Statistics on this service are more accurately tracked since all communication is being conducted in LibAnswers, which is valuable for library administration and used for organization and business planning.One potential limitation of this project was that there was only one critical appraisal expert on the EBP team; therefore, the team was unable to enlist an impartial critical appraisal expert to evaluate each individual's article selection skills. The EBP team attempted to mitigate potential bias by initiating a time delay between the critical appraisal expert's individual selection of articles and selection from the combined results, as well as documenting exclusion criteria.There are multiple issues that limit the generalizability of this QI project and Evidence Brief service. The critical appraisal expert has above average search skills for a nonlibrarian. The mid-career librarian and critical appraisal expert have taught EBP courses together for years, honing the literature searching skills of the critical appraisal expert. Also, the Value Institute is a unique department with a preexisting link between the quality department and medical library of an academic medical center. This limits the ability of another organization without this type of cross-collaboration to immediately apply the same process to create or improve an evidence synthesis service.While not many libraries have formally established EBP teams such as this one, other libraries are able to implement this process to assess the quality of librarians' literature searching and article selection skills. The EBP team feels this is a particularly effective method of establishing the literature searching skills of early career librarians, compared to those who are more experienced, and development of personalized training programs can be established based upon the results. This QI project required little additional work from the librarians outside of standard work processes, and the EBP team gained valuable insight that led to improvements in previously established work processes.


Forensic science is currently undergoing a transformation and expansion to include modern types of evidence, such as evidence generated by digital investigations. This development is said to raise a series of challenges, both in operational and conceptual dimensions. This paper reviews and discusses a series of convoluted conceptual hurdles that are encountered in connection with the use of digital evidence as part of evidence and proof processes at trial, in contradistinction to investigative uses of such types of evidence. As a recent example raising such hurdles, we analyse and discuss assertions and proposals made in the article “Digital Evidence Certainty Descriptors (DECDs)” by Graeme Horsman  200896). Section 22.1•In his conclusions, he briefly mentions ‘‘mathematical methods for quantifying evidence’’•Elsewhere, Horsman seems to acknowledge the existence of formal methods of reasoning and their use in other branches of forensic science, but questions the applicability of these methods in digital forensic science. For example, on page 2, he writes that ‘‘many other traditional forensic science disciplines are encouraged to describe the weight of their evidence in some form of quantifiable measurement/expression’’, but that ‘‘at present, there are (…) no satisfactory ways to achieve this’’ in digital forensic science.8The most visible thread in Horsman’s paper is his critique of formal methods of reasoning. As is illustrated by the following quotes, Horsman questions both the applicability of formal methods of reasoning in the context of digital evidence, as well as their existence:The author offers no tangible warrant for his claim that formal methods of reasoning cannot be enacted in digital forensic science. He makes occasional reference to other known sceptics, such as Lund and Iyer . HoweverHorsman presents these assertions as though it were clear what exactly it is in the ‘‘nature’’ [p. 3] of digital forensic evidence/science that makes this field unsuitable for the application of formal methods of reasoning, thus leaving his claim essentially unsupported.•‘‘However, any attempts to shoe-horn in such methodologies to DF where their application may not actually be feasible may be of greater detriment to this field, and provide an artificial ranking of evidence which may be misleading.’’ [p. 3]•‘‘(…) any weighting which is assigned by the practitioner which is derived purely from their own personal views is arbitrary, as previously stated, and is dangerous in terms of how a court may value such descriptions of evidence.’’ [p. 4]•‘‘A lack of any predefined statistical data regarding the likelihood of Action A or B being responsible when both remain possible means that quantify [sic] the likelihood of each is a challenge. The problem is that any assignment of likelihood to either Action to be responsible is arguably arbitrary and therefore meaningless and unreliable. Arguably, in this case it may be misleading to attempt to quantify the apparent uncertainty regarding which Action is responsible.’’ [p. 4]•‘‘(…) the inconsistent and subjective weighting of evidence.’’ [p. 8]Horsman also raises the concern of subjectivity in relation with probability , but abstains from explaining what exactly subjectivity means and does not mean in this context.These are stark assertions, but as we will show below, they misrepresent the meaning of subjective or personal probability and its role as part of formal methods of reasoning. This is a hindrance for an informed discourse on the topic and amounts to an unsubstantiated reproach against formal  methods of reasoning. This calls for a clarification.2.2being uncertain about something’’ [emphasis added] of the present, past or future. By now, the attentive reader should have noticed a first key point: dealing with and, in particular, measuring uncertainty amounts to coping with a human condition; i.e., strength of belief in the truth or otherwise of a proposition of interest. Hence, it is little surprising that the process of dealing with uncertainty involves personalistic traits. One may wonder, thus, why there is so much discomfort among scientists against the personalistic nature of the measure of uncertainty. Denying this nature essentially amounts to denying reality. We discuss possible reasons for this reaction below.It is helpful to start our discussion with a clear statement of the notion of uncertainty. Although this may seem unnecessary, because the term is almost ubiquitously used in everyday language, insisting on two related but distinct components to the term uncertainty will be beneficial for the understanding of subsequent argument. First, in a nutshell, uncertainty means ‘‘the extent of our own knowledge and ignorance’’ , p. xvi.measurement, because ‘‘[…] it is by measuring things that we know them.’’ . His key assertion is that pressing too much on implementing a quantitative approach, i.e. more than he thinks is actually feasible, is counter-productive: this ‘‘(…) may be of greater detriment to this field, and provide an artificial ranking of evidence which may be misleading’’ [p. 3]. In the same vein, Horsman describes the expression of (subjective) probabilities (‘‘assigned probabilities based on experience and subjective judgement’’ [p. 1]), that is the ‘‘inconsistent and subjective weighting of evidence’’ [p. 8], as subject to criticism, indeed inferior to ‘‘(…) objective measures [which] are considered more favourable’’ [p. 1]. He asserts that the term subjective  means or implies being artificial, misleading, arbitrary, meaningless, unreliable or even dangerous. Note that Horsman raises all of the latter words at various instances throughout his paper, either individually or in combination; see either the quotes given above as well as the following two excerpts: ‘‘any assignment of likelihood (…) is arguably arbitrary and therefore meaningless and unreliable’’ [p. 4] and ‘‘any weighting which is assigned by the practitioner which is derived purely from their own personal views is arbitrary (…) and is dangerous in terms of how a court may value such descriptions of evidence’’ [p. 4].unconstrained subjectivism’’ [emphasis as in original]. This, however, is not how subjective probabilists who are serious about their scholarship understand and advocate the notion of subjective  assessments (of probability). First and foremost, they do not equate subjectivism with arbitrariness: the liberalany probability assignment, but a justified probability assignment.justified likelihoods’’ [emphasis as in original]. Of course, this does not prevent some forensic scientists from providing questionable forensic testimony, e.g. in terms of categorical conclusions, or even sheer denial of the potential of error, but this does not invalidate the concept of personal probability – it ignores it. The ENFSI Guideline, for example, clearly states that probabilities ought to be viewed as ‘‘conditioned on the information available to the individual who makes a probability assignment’’ ‘‘These are severe words against a single notion. But, as it stands, this account of subjective  assessments  does not properly represent what personal probability is about. Again, the point has been made repeatedly in literature and current recommendations, but the fact that it continues to be misstated warrants a brief recapitulation of a few key points. Horsman’s perspective is predicated on the assumption that subjectivism is tantamount to deliberate guesswork, elsewhere called ‘‘gnment’’ , p. 23. gnment’’ , p. 15, is based on data, that is ‘‘the technical and empirical knowledge associated with a given trace type’’  is alien to the principles and intentions of forensic evaluation and evaluative reporting.Note that there is a hierarchy stipulated here. Scientists cannot use a vague reference to training and experience (mentioned last) as a substitute to hard-wired scientific publications (mentioned first). To some extent, it is surprising that all of this needs to be stated so forcefully. In an ideal world, one would expect forensic scientists to care about the reasonableness and robustness of their statements, not least because their assertions expose them directly to scrutiny by their peers.We should also insist that criminal adjudication in England and Wales – i.e. the main subsystem – defines the activities of auxiliary forces (such as forensic science) by specifying aspects such as the expert’s duty to the court , the way that experts will deliver their scientific input  and, more importantly, the structure and content of the expert’s report . Experts will do what the court and methodological principles salient in scientific enquiry and adapted to practical purposes ask them to do: address the probability of the findings given the propositions and relevant background information, and remain silent on the probability of the propositions given the findings and background information. Opining, let alone deciding on questions of justice is not required or indeed permitted for forensic experts. Hence, Horseman’s language involving terms such as ‘‘factually prove a hypothesis’’, ‘‘conclusive fact’’, ‘‘100% proof’’ [p. 7] is unsuitable in principle for forensic scientists.By dismissing the idea of quantification as a whole, and by advocating an exclusively qualitative  frameworkCritics of subjectivism commonly invoke objectivism as the obvious solution, so does Horsman (‘‘concise representations (…) that a practitioner can objectively describe’’ [p. 6], ‘‘objective measures are considered more favourable’’ [p. 1]). This is predicated on the assumption that it is clear what objectivism means, let alone it were feasible. The dualism that lingers here is that if subjectivism is intrinsically inadequate, then its opposite, objectivism, must necessarily be good. However, the contrary is the case: no choice of a framework, method or procedure can be made without resort to at least some personal judgment ,13. ThouA scientist’s assessment thus is inevitably personalistic. It relies on a body of knowledge and data which is specific to that scientist. By highlighting the necessarily subjective nature of their assessments, and by redirecting their efforts to clarifying the extent to which these assessments are, using the words of the ENFSI Guideline, ‘‘supported by scientific research’’ , p. 16, 2.5By sidestepping probability and proposing his own ‘‘language framework which defines the terms which should be used to describe a practitioner’s level of certainty in the evidence/digital content’’ [p. 6],To be clear, the suggestion at this juncture is not that probability theory ought to be taught in the courtroom. The discussion here is about the way in which forensic scientists should make up their mind when dealing with uncertainty and assigning a value to their findings – prior to proceeding with evaluative reporting.decide on a probability assignment in a way that is logically defensible, i.e. rational. What this means, in simple terms, is to understand and formally reconstruct the problem of reporting on imperfect personal knowledge in terms of probabilities, as a personal decision problem. There is a whole body of specialised literature on this topic that arose from the study of the question of how to assess, so-to-speak, the ‘goodness’ of probability assessors  (where A and B are propositions), then, in a technically strict reading, he refers to probabilities of some evidence conditional on, respectively, propositions A and B. However, the probability of the evidence given a proposition is an inferential target that he precisely seeks to avoid. This renders his critique of probabilistic evidence evaluation internally contradictory.For what it is worth, the distinction between likelihood and probability, in statistical terms, involves different targets. Technically speaking, likelihoods pertain to hypotheses, not evidence. One speaks of likelihood of a proposition for a given (fixed) item of evidence . At the same time, the Thus, ultimately, it remains unclear which uncertainty, and measure thereof, Horsman exactly refers to: that of the findings (evidence), the competing propositions , or both. While definitional intricacies of technical language may be a reason for this vagueness, yet a deeper problem is a lack of clarity regarding the purpose of his analyses and discussion. The next section addresses this issue.3interpretation and presentation of results; the latter will be the focus here’’ .Besides conceptual shortcomings in assertions about methods for the measurement of uncertainty exposed in the previous section, Horsman’s paper involves confusion with regard to the distinct role in which forensic scientists may operate. This distinction has to do with investigation as compared to evaluation. Horsman writes that his paper deals with ‘‘the evaluation of forensic findings becomes necessary when there are two competing versions of a contested event, typically brought up by adversarial parties at trial, and when it is of interest to assess the value of the forensic findings in helping to discriminate between these two competing accounts . Clearly, in the CAI framework, this can be recognised as an instance of hypotheses generation. Horsman also proposes a scheme to provide an appreciation of the extent to which the various evidential settings involve uncertainty. In the context of the CAI framework, this would amount to ranking the various explanatory accounts in terms of their posterior probabilities.At this juncture, let us recall that the important difference lies in the form of the inference that will address, in a logical, justifiable way, the specific questions in a case. The starting point for CAI is: what are the questions/issues? Then the expert has to group these questions/issues into two categories and decide whether she has the necessary knowledge, competence and licence to provide direct answers to the questions and/or the necessary knowledge, competence and licence to provide an evaluation of the weight of evidence in favour of one of two (or more) competing propositions. The two broad forms of question/issue and inference  may well overlap and within any one case. The expert has to be acutely aware of the difference and the interplay.investigative opinions. Most importantly, and this is the critical point, CAI has never insisted on the fact that such investigative opinions must strictly and systematically be structured in strictly probabilistic terms.Having clarified the different aims and, related to that, the content, form and logical structure of examiners’ conclusions and reports , it is now possible to review Horsman’s account from a broader perspective, to examine whether his aversion to the use of probability is well grounded. In essence, what Horsman is arguing for is the sorting out of viable accounts as to how digital forensic findings (evidence) came into place. As noted above, established interpretative accounts in forensic science, i.e. CAI, have never contested such an activity for forensic examiners. Quite to the contrary, CAI has explicitly reserved room for this, in the form of This confusion is unfortunate, essentially because an acknowledgment of CAI literature should have clarified matters right away. As an aside, this discussion reveals a deeper problem of current forensic science research: the problem of disregarding fundamentals. The difficulty here lies in balancing the use of concepts from outside forensic science. Where this difficulty is avoided, resorting to  forensic science exceptionalism should come as no surprise. The importance of attaching to fundamentals, especially in forensic interpretation, has long been recognised . Thus, sFor the sake of argument, let us suppose now that the analysis in the present paper is wrong and that Horsman’s criticism indeed targeted evaluative (rather than only investigative) reporting and the impossibility to address questions regarding the probability of the evidence given the proposition. More specifically, suppose that even the most sophisticated digital forensic science expert could not address, for whatever reason, the question of the probability of the evidence given the propositions of interest in an instant case. That would be a very useful finding. It would mean that the value of the evidence could not be assessed,44.1‘‘(…) this work proposes that DF opts for the use of descriptors to indicate apparent uncertainty but refrain and accept we cannot yet quantify it. Rather than strive to numerically quantify evidence weightings, it is proposed that a more viable option is to harmonise the language practitioners use to express certainty in their findings.’’ [p. 6]Horsman’s proposed solution to the alleged inexistence and unfeasibility in principle of methods for quantifying uncertainty is a range of verbal descriptors, seeking to convey the extent of (un)certainty (‘‘the use of language as a way of expressing ‘certainty’ (…) and clarity in regards to what the language means when used’’ [p. 6]), called Digital Evidence Certainty Descriptors (DECDs):explain let alone define them raises a problem on legal grounds. Courts in England and Wales are at pains to stress that it is a general principle of English law that ordinary words are notions on which the fact-finders will decide based upon their own experience of ordinary life. Experts should therefore refrain from opining on their meaning, for they are almost by definition non-experts on the meaning of ordinary words. Lord Hughes in Golds makes a similar point when he highlighted the principle of ‘‘leaving an ordinary word alone’’.38The digital evidence certainty descriptors involve six qualifiers, ranging from ‘‘conclusive fact’’ (‘‘proof in relation to a given scenario’’ [p. 7]), various intermediate levels such as ‘‘conceivable’’ (‘‘the lowest form of certainty’’ [p. 7]), to ‘‘impossible’’ (‘‘events which cannot possibly occur’’ [p. 7]). It is worth mentioning that Horsman explains his scale by resorting to numerical expressions. For example, the descriptor ‘‘conclusive fact’’, should apply when ‘‘we are looking at 100% proof’’ [p. 7]. But since DECDs involve ordinary words, trying to The choice of the verbal terms in the DECDs scheme, their number and definition shall not be discussed here. Recalling discussion presented in Section given various competing propositions, or the uncertainty affecting propositions given  particular evidence. Following arguments exposed in Section As their name suggests, the proposed verbal descriptors (DECDs) seek to qualify the (extent of) certainty, but the target of this description is confusing. DECDs are supposed to concentrate on the evidence , yet the definition given in Table 1 (in Ref. ) on pageα is observed, conclude β’. For example, the AFTE (Association of Firearm and Toolmark Examiners) theory of identification stipulates that when there is ‘‘sufficient agreement’’ ). However, if that is the case, this falls short of the stated purpose. Recall that Horsman’s paper stated its purpose as follows: ‘‘interpretation and presentation of results; the latter will be the focus here’’ . The point we intend to make here is that interpretation and description are different topics. Conventionally, description has to do with capturing, by an observer, perceivable aspects and properties of a descriptum, that is the entity to which a description refers. Interpretation, in turn, is different in the sense that it is not descriptive, but analytical, and involves inference. As per definition, the target of interpretation, that is the meaning of evidence, is not an inherent property that could be captured in a descriptive sense. Arriving at an interpretation through description, as is the pretence of DECDs, thus amounts to a contradiction in terms. If one wishes to describe the strength (or meaning) of evidence, one first needs to work it out, which can only be achieved by interpretation, not description. Pretending the contrary would amount to what Salmon has called ‘‘epistemological magic’’ .First and foremost, the expression ‘could have/be’ induces scientists to opine on the plausibility of propositions  which, as exposed in Section ‘‘(…) the answers provided by the experts, when formulated in words, tend to be rather elusive. Typically experts give evaluations like: ‘‘It is almost certain, but not sure; indeed it might not be the case.’’ and so on. They say and unsay in the one breath, not to risk too much. The result is that it is never quite clear what their answers mean. The expert tries to speak in such a way as to secure himself that, whatever happens, one cannot tell him that he was wrong. On the contrary, if questions are asked in such a way as to obtain a probability value as an answer, the ambiguity disappears.’’ , p. 8In combination, the above observations reveal a key insight: avoiding quantitative expressions through the use of qualitative verbal expressions will leave recipients of expert information clueless about the strength of one’s message, to the point of being a statement of the obvious.Clearly, forensic scientists should aim at a reporting language that offers more than qualitative vagueness. The way out of the impasse of qualitative wording, however, does not come effortlessly. It brings us back, as noted in the above quote, to the fundamentals of the scientific approach to uncertainty measurement, which is probability.A further way to understanding this argument is to ask: Why do we need to hire an expert? The answer is that one resorts to experts whenever one seeks an assessment for an issue that lies beyond one’s area of expertise. Experts’ assessments can take many forms, of course, with the lowest level of assessment often being regarded as one coarsely referring to possibilities. However, we should ask how useful a mere statement of possibility is. Suppose that all an expert would be able to say is that it is possible to observe this evidence if proposition A were true, but that is also possible to observe the same evidence in the event that another proposition, B, were true. To be clear, there are situations in which this is all that can meaningfully be stated – i.e. a case in which the evidence would have no probative value – but this should not be taken to mean that reporting language in terms of mere possibilities should set the bar. The truth is that it is by quantification that we make our way through the world: at the end of the day, humans in their professional activities as well as in other matters regarding their daily lives must make decisions whose consequences depend on uncertain states of nature, that is probability. This is not to say that a probability needs to be framed in full quantitative terms . An order of magnitude may be sufficient to be useful e.g., .42 Contra lot means for me? – Give me the number!’.To illustrate this point, suppose being told that you won the lottery. This may be little helpful for you as your immediate question will be ‘How much?’. Suppose further that the answer you receive is something like ‘a lot’, ‘sufficiently much’, etc. At this point, you may end up being annoyed and ask ‘How do you know what not arguing that in a rationality-driven world, everyone should necessarily use probability in a fully numerical or computational way. Often, targeting an advanced level of detail or consideration of a densely related collection of variables will pose operational difficulties. Practical decisions are typically responsive to many variables, thus making computation come at the price of efficiency, or even worse: analysis paralysis. We also make no prescriptive claim of how exactly evaluative reporting should be formulated in practice . Our co in Ref. , p. 121.are saying is that probabilistic expressions can take the form of both numbers and words. The most important evidential test in law, that of relevance, depends on the tendency of an evidence item to make a proposition more or less probable. Probabilistic judgments by participants of the legal process, whether on relevance, degree of persuasion or aspects of forensic expertise, and whether numerical or verbal, have a quantitative connotation. The role of numbers is to substantiate comparisons. Hence, DECDs decidedly fall short of the point. What matters, though, is the way they miss the point. As outlined above, the proposed verbal descriptors are not inherently useful or useless. The insurmountable problem is, we think, that these six descriptors do not really describe anything insofar as they lack grammar. They are void of rules or standards of usage despite their ad-hoc description given in Table 1 [in Ref. [What we [in Ref. ]: anyone5A new expression, ‘digital transformation’, has become fashionable and is currently circulating in forensic science. It is associated with forensic science encountering novel forms of evidence, especially digital evidence. It is argued that such evidence implies distinct challenges. For example, Horsman mentions ‘‘the nature of digital evidence and investigations of this type’’ [p. 3], in particular ‘‘intricacies of digital data’’ [p. 1], as reasons why ‘‘a scientific mechanism for quantifying digital evidence may not actually be feasible’’ [p. 3]. He also argues that ‘‘attempts to quantify any uncertainty should be abandoned’’ [p. 1]. As shown throughout the present paper, this viewpoint is wide of the mark, and misconceives the notion of probability on several fundamental aspects. The discussion in this section seeks to summarise two main points and place them in a wider perspective. This will lead to conclusions that depict an alternative view on what the pending challenges in  forensic science are.not to commit the failures and shortcomings in evidence interpretation that (continue to) affect traditional forensic disciplines. However, this would require the community of researchers and practitioners to draw suitable conclusions from the principles of forensic interpretation that have been developed since the middle of the last century. The DECD conclusion scale that replicates an inferentially problematic design seen previously in forensic science . From anormative requirements, both methodological and procedural in nature, which forensic fields ought to fulfill. A set of descriptors that lack an underpinning conceptual framework which could regulate usage in practice is sidestepping the requirement for justification. A lack of accountability represents a loss, as it removes justifications and reasoning processes entirely from the public arena. If this is what  forensic science is or aims at, then it is difficult to see how it can meaningfully serve the needs of fact-finders in the pursuit of justice.How can a forensic branch get this far? In our view, a recurrently invoked pattern of argument to avoid engagement with primary concepts is claiming exceptional status. It has already been observed elsewhere before in forensic science and we also see it nowadays occurring in the context of digital forensic evidence. The claim, however, that digital forensic science is inherently different from other forensic branches that abide by scientific principles does not meet the The authors declare that this paper was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.