Polypharmacy is a common issue in patients with chronic diseases. Eastern-European countries and Iran are exploring possibilities for implementing the Medication Use Review (MUR) as a measure for optimizing medication use and ensuring medication safety in polypharmacy patients. The aim of this study was to gain insights into the development of the community pharmacy sector and map facilitators and barriers of MUR in Eastern Europe and Iran. The representatives of the framework countries received a questionnaire on community pharmacy sector indicators, current and future developments of pharmacies, and factors encouraging and hindering MUR. To answer the questionnaire, all representatives performed document analysis, literature review, and qualitative interviews with key stakeholders. The socio-ecological model was used for inductive thematic analysis of the identified factors. Current community pharmacist competencies in framework countries were more related to traditional pharmacy services. Main facilitators of MUR were increase in polypharmacy and pharmaceutical waste, and access to patients’ electronic list of medications by pharmacists. Main barriers included the service being unfamiliar, lack of funding and private consultation areas. Pharmacists in the framework countries are well-placed to provide MUR, however, the service needs more introduction and barriers mostly on organizational and public policy levels must be addressed. In older patients with multiple chronic diseases, polypharmacy and drug-related problems are increasingly serious concerns. Polypharmacy patients have an increased risk of experiencing adverse drug reactions, geriatric syndromes, morbidity, and decreased medication adherence. Polypharmacy patients also receive inappropriate medications more frequently . AlthougTo support appropriate polypharmacy and ensure medication safety, many pharmacist-led services have been developed worldwide. Pharmacist-led medication review (MR) is a structured evaluation of a patient’s medicines for detecting drug-related problems and recommending interventions with the aim of optimizing medicine use and improving health outcomes . MR servDifferent types of MR services such as medication therapy management, home medicines review and medicines use review have been offered by community pharmacists in United States of America, Australia, New Zealand, and United Kingdom for many years ,10,11,12One of the first Eastern-European countries to provide a nationally approved and funded MR service in community pharmacies was Slovenia in 2015 ,16. In rThe aim of this study was to map and analyze healthcare and pharmacy sector indicators facilitating and hindering provision of the Medication Use Review (MUR) service in Eastern-European countries and Iran.Simple MUR conducted in a community pharmacy by a community pharmacist; the pharmacist receives information about the medication regimen and patient’s diseases from the patient in a face-to-face interview and their general practitioner (GP); the service focuses on educating the patient on their diseases and medicines and detecting issues related to medication adherence and manifested drug related problems.Comprehensive MR conducted in a community pharmacy by a community pharmacist who has passed an additional course in clinical pharmacy; additionally, requires information on the clinical test results from the GP as the pharmacist also evaluates the medication list for potential drug related problems.MR service provided by a clinical pharmacist in the hospital setting; the clinical pharmacist additionally gets involved in establishing the treatment regimen for the patient .Background information: In September 2017, a working group of pharmacists, general practitioners, and key stakeholders from both healthcare and the pharmacy sector was established in Estonia with the aim of developing a standard for the MUR service and identify possibilities for the implementation of the above-mentioned service. In 2018 the Estonian MR standard was adapted and amended from the 2013 Pharmaceutical Care Network Europe statement for medication review . The adaIn January 2019, the MUR pilot project started in Estonia and in March the international MUR network consisting of 11 countries  was launched to look further at the opportunities for advancing the MUR service on the first level according to the adapted standard, which can also be considered Type 2 MR according to Hatah et al. 2014 meta-analysis .Country indicators: total population, gross national income per capita, life expectancy at birth male/female, quality life years male/female, total expenditure on health as percentage of gross domestic product—GDP (%), pharmaceutical spending as a percentage of health spending (%); share of population aged 65 and over (%), long term illness in elderly population (%).Pharmacy sector indicators: number of community pharmacies; number of community pharmacists; number of assistant pharmacists at community pharmacies.Current and future competencies and roles of community pharmacists; recent and future developments in community pharmacies.Factors which are facilitators and barriers to MUR.Study instrument: In September 2019, representatives of all 11 MUR framework countries received a study instrument compiled by researchers and practicing pharmacists from Estonia and consisting of the following questions: To complete the questionnaire, the representatives of the MUR network were asked to use existing information and data sources specifically: literature review, document analysis and qualitative interviewing of key stakeholders . Interviews were conducted to answer the third and fourth question and were recorded by written notes. In May 2021, all representatives were asked for follow-up details on recent developments in the pharmacy sector and pharmacist’s role. Ethics committee approval was not sought for this type of research, as the data collected for the study are not sensitive personal information, nor were any interventions conducted on the study participants. All participants were informed their answers will be used in the study and their anonymity will be guaranteed prior to the interviews.Data analysis: the parameters of pharmacy sector and country indicators for Iran were different from the Eastern-European framework countries and thus were not included in equations for expenditure on health, share of elderly population and community pharmacy sector indicators.The social ecological model (SEM) including individual, interpersonal, institutional/organizational, public policy, and social domains  was adapAnswers were collected in November 2019 from nine out of the eleven framework countries namely Croatia, Estonia, Latvia, Lithuania, Hungary, Poland, Iran, Slovakia and Romania.An overview of the country profiles is shown in Current competencies and roles of community pharmacists in all MUR framework countries include dispensing and counselling of prescription and over-the-counter medicines and compounding of extemporaneous medicines. Pharmacists also offer reporting or patient assistance in reporting adverse drug reactions, and patient education on disease prevention and maintenance of health in most framework countries. Usually, some point-of-care testing is provided . In Lithuania, community pharmacists are offering an asthma management service and patient education on inhaler use techniques. In Croatia, pharmacists are improving patients’ medication adherence by counselling service and sorting patients’ medicines into weekly dispensers, and recently started dispensing biological therapies and counseling patients regarding their safe and proper use.Most often named future competencies of community pharmacists in framework countries were provision of extended services such as MR, influenza vaccination, diabetes screening, smoking cessation, international normalized ratio (INR) measurements, and new medicines service. Additionally, in Poland, performing simple diagnostic tests such as blood pressure monitoring, cholesterol and glucose measurements is expected to be a future competency.The primary recent development in the pharmacy sector for Estonia and Hungary was the ownership reform of community pharmacies and prohibition of vertical integration between wholesale and retail sale of medicines. Recent development for Romania includes an online pharmacy which dispenses over-the-counter medicines and parapharmaceuticals. For Poland, the recent development would be introduction of an E-Prescribing system.Both Croatia and Estonia have been actively participating in the development of the electronic cross-border health services, which allows continuity of care for EU citizens while travelling abroad in EU. By 2021, both countries have implemented the electronic cross-border e-prescription system and are one of the first countries to do so.Croatian working group also named several new regulations in pharmacy policies as a future development and by 2021, Croatian government has proposed the National Recovery and Resilience Plan for 2021–2026 which includes monitoring the outcomes of outpatient treatment and controlling and preventing medicine shortages in community pharmacies.Future plans for Iran include an E-Prescribing system reaching everywhere in the country. In Lithuania, it was planned to introduce a state-run pharmacy network where state-owned hospital pharmacies would have outpatient departments to fulfil community pharmacy duties.In the project countries, the most often cited factors that were facilitating MUR were increase in polypharmacotherapy and pharmaceutical waste and access to an electronic list of medicines and medical records by pharmacists. The most often reported barriers were the service being unfamiliar to both physicians and pharmacists, the financing model of MUR, high workload in pharmacies and lack of private consultation rooms for MUR service in some community pharmacies. The SEM analysis detects which factors are currently facilitating or hindering the implementation of MUR in the practice of a community pharmacist. For the SEM analysis of facilitators and barriers, see The development of the pharmacy sector in Eastern Europe and Iran could be considered similar. Pharmacist competencies mostly include providing traditional services such as dispensing, consulting and compounding, and there has been little development in pharmacist role regarding extended services so far. Thus, the barriers and facilitators of MUR service for the community pharmacist in these countries can be described jointly.In framework countries, the initiative to introduce MUR has come from academics and active pharmacists, who understand that both polypharmacotherapy and pharmaceutical waste are serious concerns in the region, which have not been properly addressed by government institutions . For comFunding the service could prove to be difficult to overcome, as the average expenditure on healthcare in Eastern Europe and Iran is lower than the European Union average of 9.9% in all framework countries . This miAccess to digital records of the patient’s medications is vital in order to be able to offer the MUR service and has been cited as a prime encouraging factor in previously published literature . In someThe COVID-19 pandemic might have encouraged implementing pharmacist-led extended services on the public policy level in some countries. As an example, Polish community pharmacists can now independently prescribe medicines to themselves and their own family members .One of the main barriers to MUR at the organizational level is the high workload of pharmacists. This issue could be solved by hiring more pharmacists, although the structure of the pharmacy sector in framework countries does not support this solution. In most framework countries, the number of patients per community pharmacy is rather low, while there are few pharmacists per community pharmacies. The large number of community pharmacies might hinder the development of MUR considering that it would therefore be difficult to find the additional workforce necessary for the extended services.Other important organizational factors include lack of private rooms and electronical resources such as computers in community pharmacies. Community pharmacy owners might be more willing to invest in solving these organizational problems if the service received national remuneration. However, previous research has shown that lack of pharmacy staff, prioritization of other clinical activities and dissatisfaction with the consultation area seem to be persistent issues even in countries where MR has been funded ,17,30.Pharmacy chains have been known to promote implementing extended services such as MUR, especially with national funding. Promotion of MUR by pharmacy chains, however, contributes to the quality of the service being more questionable in the eyes of other healthcare professionals . Some frInsufficient collaboration between general practitioners and pharmacists was reported as a barrier by only two framework countries. For the pilot in Eastern Europe and Iran, motivated and supportive physicians were included early on, which might have caused the misconception that opposition to the service by general practitioners would not be an issue. In previously published literature, lack of collaboration between healthcare professionals is often highlighted as one of the main barriers ,17,30. TMUR is still unfamiliar to many pharmacists and other health professionals, who could direct their patients to receive the service. More pharmacists need to provide MUR in order to normalize the service in the health sector. It is important for health workers to understand the potential benefits and have a positive experience with MUR to refer their patients to the service routinely. Thorough introduction is necessary for effective implementation of MUR in the framework countries.According to the international vision and policy, the provision of professional services should be a priority for pharmacies and health systems. As with other health innovations, the implementation of professional pharmacy services is complex and represents an area in which pharmacy in the community has had limited experience . Skills Key stakeholders in Eastern Europe and Iran are exploring the possibilities to apply extended pharmacy services such as MUR into practice. As an increase in polypharmacotherapy and pharmaceutical waste are increasing concerns in MUR framework countries, it is important to routinely assess patients’ medication use. More health professionals need to be introduced to MUR and interprofessional practice which supports pharmacists working together with GPs. Pharmacists are in many ways well placed to provide MUR; however, it is necessary to gain government support and financing for the service in Eastern Europe and Iran. Several organizational barriers such as high workload and lack of private consultation rooms, as well of the lack of standards for the service need to be addressed for continuing with MUR.


Based on a weak  recommendation, the panelconcludes that “In elderly (75 years or older) patients living in Latin America withsevere symptomatic aortic stenosis (AS) candidates for transfemoral approach, the panelsuggests the use of TAVI over SAVR”. This guideline has been put together and funded bythe Sociedad Latinoamericana de Cardiologia Intervencionista (SOLACI) with theendorsement of the Sociedad Interamericana de Cardiologia (SIAC). As stated by theauthors, the rationale for this document emerges as a response to their disagreementwith the decision made by the cost-effectiveness technology assessment agency inArgentina, which defined the use of transcatheter aortic valve replacement forinoperable patients. The aim was “to develop a high-quality and transparent guideline tohelp physicians and other stakeholders concerning the use of TAVI versus SAVR in LatinAmerica”. Despite the authors’ thorough job reviewing the existing internationalevidence according to the Grading of Recommendations, Assessment, Development andEvaluations (GRADE) criteria and the relevant systematic review, these recommendations,which stem from Latin-American authors, are not specifically for Latin America.The Heart journal, from the British Medical Journal and the British CardiovascularSociety, has recently published a review titled “Clinical practice guideline fortranscatheter (TAVI) versus surgical aortic valve replacement (SAVR) in patients withsevere aortic stenosis in Latin America”The Latin American Association of Cardiac and Endovascular Surgery (LACES) nucleates over400 members of the Latin-American continent. It started in 2019 and is currently themost inclusive cardiac surgical association in Latin America, recognized by the EuropeanAssociation of CardioThoracic Surgery, Society of Thoracic Surgeons, AmericanAssociation of Thoracic Surgery, and Association of Thoracic and Cardiovascular Surgeonsof Asia. Based on the following issues, this association does not support theSOLACI/SIAC recommendations..Extrapolating data from a different socioeconomic reality with different hospital volumeexperiences to our continent is dangerous for our patients and the health economicsystem. When the aim is to perform regional guidelines, as in the title of this review,it is critical to consider the regional context; if not, this review may well apply toAfrica, Europe, America, Asia, or Oceania. The authors explicitly disregardedLatin-American evidence under the assumption that the conclusions were “erratic”. Notincluding regional evidence is a significant flaw and suggests serious selection bias inthe evidence process.A guideline to help physicians and stakeholders decide the best course of action in LatinAmerica must come from Latin-American effectiveness data. It is impossible to recommendsomething for our region when we do not know what is going on. The effectiveness of aprocedure depends not only on the procedure, per se, but also on the socioeconomicreality, which directly affects our patients and is the basis of the cost-effectivenessanalysis. Several reports have highlighted the importance of hospital and technicalvolume to assure good outcomes-.To begin with, the document fails to examine critical and recent evidence and makerecommendations in line with the goals of treating heart valve disease. The treatment ofAS should be accomplished aiming to restore long-term life expectancy and improvequality of life, avoiding detrimental late events reversing the early success of theprocedure. For now, only SAVR is established to restore the prognosis of patients withsymptomatic severe AS, with long-term postoperative survival becoming comparable to anage- and sex-matched general population without AS in patients over 65 yearsold. The report of thefive-year outcomes of the Placement of Aortic Transcatheter Valve (PARTNER) 2 cohort Atrial found a higher risk of death or disabling stroke between two and five years afterTAVI than after SAVR, with a hazard 27% higher,. Themeta-analysis by Barili et al. with Kaplan-Meier-estimated individual patient dataevaluating the effects of TAVI and SAVR on the long-term all-cause mortality raterevealed a lower incidence of death in the first year after TAVI. In contrast, there wasa reversal of the endpoint after 40 months favoring SAVR over TAVI. The mortality ratesin trials of TAVI vs. SAVR are affected by treatments with atime-varying effect and TAVI is related to better survival in the first months afterimplantation whereas, after 40 months, it is a risk factor for all-causemortality.The SOLACI/SIAC document implicitly assumes an equipoise between long-term outcomes ofTAVI and SAVR, which has been challenged by recent evidence. In this way, the results ofrandomized controlled trials, metanalyses, and national databases show theopposite.In the PARTNER 3 trial, the event-rate lines for death and disabling strokes, whichsignificantly favored TAVI in the one-year analysis, from the two-year follow-up, thecurves are converging over time, and reversal of fortunes may become tangible in thelonger-term.The German Aortic Valve Registry (GARY), assessing the long-term outcomes of aortic valvereplacement with TAVI and SAVR, revealed that after propensity score matching, TAVI withearly generation prosthesis was associated with significantly higher five-year all-causemortality than SAVR, reaffirming earlier data from Italian and French nationwideregistries. Additionally, the curves for survival probability keep diverging over time,hinting at a longer-term worse prognosis for patients who underwent TAVI procedure. Thefinding from the GARY registry is worrisome as it raises the further question of whatcould be done to low- and intermediate-risk patients who had TAVI implanted and now mayface shorter life expectancy.The recommendation for TAVI in patients over 75 years old is unrealistic, given that thelife expectancy for men and women aged 75 is a further 11.18 and 12.97 years,respectively, therefore the long-term benefit of the procedure would be adverselyaffected cutting short late survivalDuring all these years, different centers from Latin America have generated essentialdata to produce high-quality effectiveness results and therefore adapt recommendationsto our reality. We consider this is critical to produce trustworthy recommendations andinform stakeholders on the best action to take. Our association has always been open toworking in a multidisciplinary team objectively to produce and analyze these data. Webelieve this is the initial step before making any regional guideline.Severe conflicts of interest (COI) generate undisputed bias. Despite the fact thatsurgeons have proficiently been treating aortic valve stenosis for more than 60 years,no cardiovascular surgical association was invited to take part in this document. Theauthors mention that no surgical association exists in Latin America, which shows anapparent disrespect to LACES and the concept of Heart Team..In fact, surgical cardiovascular societies have been recurrently excluded from makingTAVI guidelines, raising the suspicion of primary stealth financial interest behindthis. The methodologist and principal investigator, Dr. Lamelas, hasheavy COI with Edwards, Medtronic, and Boston Scientific. The voting panel included fourmembers who are proctors for these companies as well. The methodology team, led by Dr.Lamelas, decided that “TAVI proctoring may not be a strong financial conflict ofinterest”. We strongly disagree with this decision and believe that Latin America hassurgeons and interventional cardiologists with robust academic experience and withoutCOI who are not proctors for the industry with the capacity to evaluate the evidence andprovide an objective vote.Citing Gordon Guyatt from GRADE, “We believe that the key to developing conflict-freerecommendations is that panel members without conflicts and, in particular, themethodologist chapter editor, bear responsibility for the final presentation of evidencesummaries and rating of the quality of evidence. The chapter editor is also responsiblefor ensuring that, during the discussion of evidence, panel members with conflicts donot take an aggressive advocacy role”The authors mention that they did not involve SOLACI authorities in the process of theguidelines. This assertion is unclear since the principal investigator (PL) is thecoordinator of research in SOLACI, and one of the external reviewers, Oscar Mendiz (forwhom the COI are not disclosed), is part of the counseling committee of SOLACI.The authors have mentioned but not analyzed the role that costs have on TAVIimplementation in Latin America. They propose to waive taxes on TAVI as a solution forthis limitation. Considering that the GRADE approach requires a multidisciplinary teamwith specific skills, it would have been critical to have experts from healthcare andhealth technology assessment from Latin America among the guideline team..National per capita expenditures on health vary widely in Latin-American countries, witha mean of USD PPP 1,025, ranging from less than USD PPP 500 in some countries of CentralAmerica and the Andean region , to aroundUSD PPP 1,138 in Mexico, USD PPP 1,280 in Brazil, USD PPP 1,907 in Argentina, and USDPPP 2,484 in Cuba. These figures are in sharp contrast with the average Organisation forEconomic Co-operation and Development (OECD) countries and United States of America 2019health spending per capita of USD PPP 4,223 and USD PPP 11,071, respectively.In times of extreme pressure on health resources, regardless of the countries’ economicposition, adopting a new technology that is five to 10 times more expensive than theexisting standard, with inferior results, seems illogical and requires seriousreflectionIn summary, despite the extensive review of the current evidence of TAVI and SAVR, webelieve the authors failed to examine the existing evidence from Latin America,comprehensively. Heavy COI in members of the voting panel and from the chair of theguideline (PL) make the process and recommendations unrealistic and biased. We believeguidelines should meet three essential requisites:Be based on the reality of the region where it intends to be appliedBe led, as GRADE suggests, by an independent group of investigatorsFollowing GRADE recommendations, including experts from all criticaldisciplinesFurthermore, accurate and trustful information to patients and their family should bemade available - the risks involved, the benefits afforded, and the expected long-termprognosis.The extensive financial COI may unduly influence professional judgments, interfere withthe appraisal and recommendation of the Heart Valve Team, and discredit the integrity ofscience, the quality of care, and public confidence in medicine. There is a debate thatsurgical and medical societies should compulsorily embrace and coordinate their effortsregarding the response to flawed trials and unrealistic guidelines.LACES is open to working jointly for this and future guidelines under GRADE methodologyand led an independent GRADE expert group. The stand taken by the Heart journalpublishing the pretense SOLACI/SIAC guidelines with all the raised biases istroublesome. This document has been submitted as a Letter to the Editor to the Heartjournal in response to its publication and, since no response was received afterrepeated e-mail contacts to the editorial office, a decision was made to submit it tothe Brazilian Journal of Cardiovascular Surgery.


The experience of eating is inherently multimodal, combining intraoral gustatory, olfactory, and somatosensory signals into a single percept called flavor. As foods and beverages enter the mouth, movements associated with chewing and swallowing activate somatosensory receptors in the oral cavity, dissolve tastants in the saliva to activate taste receptors, and release volatile odorant molecules to retronasally activate olfactory receptors in the nasal epithelium. Human studies indicate that sensory cortical areas are important for intraoral multimodal processing, yet their circuit-level mechanisms remain unclear. Animal models allow for detailed analyses of neural circuits due to the large number of molecular tools available for tracing and neuronal manipulations. In this review, we concentrate on the anatomical and neurophysiological evidence from rodent models toward a better understanding of the circuit-level mechanisms underlying the cortical processing of flavor. While more work is needed, the emerging view pertaining to the multimodal processing of food and beverages is that the piriform, gustatory, and somatosensory cortical regions do not function solely as independent areas. Rather they act as an intraoral cortical hub, simultaneously receiving and processing multimodal sensory information from the mouth to produce the rich and complex flavor experience that guides consummatory behavior. Eating is a multisensory experience , there is evidence for taste-somatosensory interactions as early as the peripheral taste-receptor cell , paying particular attention to studies examining the direct corticocortical connectivity between them. Second, we review neurophysiological findings detailing how the three cortical regions represent and process their unimodal component of flavor. Lastly, we discuss the evidence from recent studies highlighting the capacity of the three sensory cortical regions to process multimodal information related to flavor. Throughout this review, we will emphasize the critical gaps in knowledge that require further investigation to better understand the neural substrates underlying the multimodal processing of flavor.odorants or odors, reach olfactory sensory neurons localized in the main olfactory epithelium via two routes. Orthonasal olfaction occurs when odors are inhaled through the nares directly into the nasal cavity . Retronasal olfaction occurs when odors travel from the mouth, passing through the orophyranyx, activate olfactory receptors in the nasal epithelium  present in foods and beverages. In rodents, information related to the chemical identity and the hedonic properties of taste stimuli is carried by cranial nerves V, VII, XI and first processed by two brainstem nuclei, the nucleus of the solitary tract (NST) and parabrachial nucleus (PBN), before ascending to the gustatory thalamus  , these studies showed that neurons in the gustatory cortex represent the identity and hedonic value of taste stimuli. Neurophysiological data obtained from extracellular recordings in anaesthetized and alert rodents highlight the presence of both narrowly-tuned neurons  and broadly-tuned neurons  , interposed by large cortical areas void of activity. Conversely, a study in anaesthetized rats using intrinsic imaging  in anaesthetized mice  has been extensively studied, few experiments have investigated the cortical organization of somatic inputs from the oral cavity. Early electrophysiological studies in anesthetized rats provided the first experimental evidence of intraoral tactile-evoked neural activity within the lateral somatosensory cortex Welker, . Of partTraditional theories of multisensory integration propose that information from different sensory modalities is first isolated and processed by the primary sensory cortical regions before being integrated by higher-order areas  and R01-DC018273 (CS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Arthroereisis is a surgical procedure primarily used to treat flexible pes planus (flatfoot) in pediatric and young adult patients. The principal goal of subtalar arthroereisis is to relieve pain and restore function. This is primarily done by restoring the medial foot arch without fusing the subtalar joint and without requiring a long recovery period needed after osteotomies. Although the procedure can be performed in isolation to treat flexible flatfoot, it can also be performed as an ancillary in the treatment of tarsal coalition, posterior tibial tendon dysfunction, and accessory navicular syndrome. Various implants and multiple surgical techniques exist for arthroereisis, such as the sinus tarsi implant and calcaneo-stop. The type of device and the surgical approach to proceed with are based on the surgeon’s discretion rather than an evidence-based protocol. Multiple complications can arise from subtalar arthroereisis, most commonly sinus tarsi pain. Currently, there is a dearth of quality clinical data and evidence on the long-term outcomes and complications of arthroereisis. This lack of literature for a commonly performed procedure validates the need for future studies to better guide a standard protocol, reach consensus on well-defined indications and contraindications, provide expected complications, and improve the practice of evidence-based medicine. Anatomy of the subtalar jointThe subtalar joint articulates the talus, calcaneus, and navicular bones of the foot Figure . The funThe subtalar joint holds three articular facets on the superior calcaneus and inferior talus, all of which vary greatly in size and shape. Functionally, during normal gait, supination of the subtalar joint locks and transforms the foot from a position for shock absorption to a mechanical lever that aids the foot in propelling the body forward. Proper alignment of the articular facets, ligaments, talus, navicular, and calcaneus on the subtalar joint axis is essential to the physiology of all steps of human gait .Pathology of flatfootPes planus, the primary condition for which arthroereisis is performed, occurs due to the abduction of the forefoot, excess subtalar eversion, and resultant loss of the medial longitudinal arch of the foot . PediatrTreatmentThe initial management of pes planus includes exploring all conservative measures as many pediatric patients go on to have no long-term issues with minimal intervention. Conservative measures include rest, anti-inflammatory medications, physiotherapy, and orthotics. However, if pain persists and there are functional ambulatory difficulties affecting daily life, operative treatment may be indicated . NumerouHistoryThe initial discourse on surgical alteration of the tarsi and the subtalar joint arose in 1946 when Chambers suggested correcting flatfoot by placing a wedge upon the superior surface of the calcaneus to restrict the anterior displacement of the talus from the calcaneus . The firDesign classificationThe modern classification of subtalar implants used in the arthroereisis procedure is based on four critical aspects of the device: shape, anatomic orientation within the tarsal sinus, location the device is anchored within the sinus, and mechanism of talar stabilization . ImplantThe popularity of the procedureThe subtalar arthroereisis was widely adopted during the 1970s but has since fallen in and out of practice . DespiteAnatomical and mechanical effects of arthroereisisSinus tarsi implants placed during subtalar arthroereisis procedures have not been found to alter the anatomy of the subtalar joint or press against articular joint cartilage. With the exception of the subtalar peg, the implant rests entirely within the sinus tarsi . A systeSurgical indicationsThe primary indication for subtalar arthroereisis is the non-fusion treatment of more symptomatic forms of pediatric flexible pes planus (flatfoot). Although there is no consensus on the treatment of pes planus, one of the main surgical recommendations to relieve pain and improve function is subtalar arthroereisis . SubtalaTahririan et al. differentiated between two subtypes of flexible pes planus in pediatric and young adults to help guide the treatment plan. First, those with marked forefoot abduction can be better managed with lateral column lengthening . Second, those with limited forefoot abduction but excessive subtalar eversion can be better managed by arthroereisis .ContraindicationsSubtalar arthroereisis has mainly been used to correct flexible flatfoot. In fact, rigid pes planus may contraindicate the use of arthroereisis as the primary surgical procedure . Other cSinus tarsi implant techniqueThere are multiple techniques and approaches to arthroereisis surgery, which is typically completed within 20 minutes . The proCalcaneo-stop techniqueOne of the methods of arthroereisis is known as calcaneo-stop. First introduced in 1995 by Alvarez, the calcaneo-stop method aims to limit subtalar joint motion via a screw inserted into the calcaneus. This approach to arthroereisis is less expensive and results in similar improvements in pain and function. Similar to the previous technique, calcaneo-stop utilizes the sinus tarsi for entry . In thisAnother method of arthroereisis, also with beneficial results, describes drilling and implanting a screw into the lateral side of the talus rather than the calcaneus. Complications of this approach, according to a study by Scharer et al., include 15% reoperations due to implant migration, undercorrection, and overcorrection .Tips and tricksFirst, fluoroscopy should be used throughout the procedure to ensure the adequate position of the implant. Second, the lateral part of the implant should be at least 1 cm medial to the lateral edge of the calcaneus. Third, overstuffing of the sinus tarsi should be avoided. Finally, the guidewire should be clamped on the medial side to avoid backing out during trials.Implant removal and position of the foot post-removalThe chief cause prompting the removal of an arthroereisis implant is postsurgical pain in the region of implantation. In adults, for instance, the incidence of sinus tarsi pain has been reported in as many as 46% of cases. Many times, the pain was severe enough to warrant implant removal. However, a notable and intriguing benefit to arthroereisis is the minimal, if any, loss of flatfoot correction after removal . Chong eProcedural outcomesSeveral systematic review articles have investigated the outcomes of subtalar arthroereisis in the pediatric population. We reviewed three recent systematic reviews on the outcomes of subtalar arthroereisis by Tan et al. , MetcalfAnother common method to gauge the success of the procedure is to measure radiologic criteria. Table Previous studies have also demonstrated a reasonably high level of patient satisfaction. Tan et al. found that 66.8% of the patients rated it excellent, 22.1% rated it good, 5.0% rated it fair, and 6.0% rated it poor . MetcalfComplicationsWhile subtalar arthroereisis has certain benefits for primary and secondary flatfoot-related foot pain and stabilizing the subtalar joint into its proper orientation, it is not without its drawbacks. In a systematic review of 76 studies, complication rates ranged from 4.8% to 18.6%. Most notably, between 7.1% and 19.3% of these surgeries had an unplanned implant removal . Some ofAdvantagesMany of the advantages of arthroereisis are related to its relatively low level of invasiveness and easy reversibility compared to other procedures. For example, osteotomy carries with it risks inherent with bone grafts and changing the biomechanics of the foot. Osteotomies can result in calcaneocuboid subluxation, non-union or delayed union, or sural nerve injury . ArthroeArthroereisis has shown statistically significant improvement in the primary correction of flexible pes planus in pediatric patients and is effective as an adjunctive procedure in accessory navicular syndrome, tarsal coalition, and posterior tibial tendon dysfunction. While complications such as sinus tarsi pain and undercorrection occur in some patients, in cases of severely painful flatfoot refractory to non-surgical intervention, this surgery may be indicated after thorough discussion with the patient regarding all possible outcomes. Further, due to the high degree of reversibility, with adverse symptoms often resolving after implant removal, arthroereisis is considered a relatively safe procedure for persistent flatfoot pain. The subtalar arthroereisis surgery, nonetheless, requires future long-term prospective studies examining the biomechanics of the procedure and implant, as well as forthcoming complications. Given its current conventional use and potential for improvement, subtalar arthroereisis can undergo immense progress regarding establishing evidence-based clinical guidelines and reaching a better consensus on how to optimize this surgery.


A core evaluation framework that captures the health care and societal benefits of value added medicines  was proposed in Report 1, aiming to reduce the heterogeneity in value assessment processes across countries and to create incentives for manufacturers to invest into incremental innovation. However, this can be impactful only if the framework can be adapted to heterogeneous health care financing systems in different jurisdictions, and the cost of evidence generation necessitated by the framework takes into account the anticipated benefits for the health care system and rewards for the developers.The framework could potentially improve the pricing and reimbursement decisions of VAMs by adapting it to different country specific decision-contexts such as deliberative processes, augmented cost-effectiveness frameworks or formal multi-criteria decision analysis (MCDA); alternatively, some of its domains may be added to current general evaluation frameworks of medicines. The proposed evaluation framework may provide a starting point for practices based on which VAMs can be exempted from generic pricing mechanisms or can be integrated into the reimbursement and procurement system, allowing for price differentiation according to their added value. Besides evidence from RCTs, pricing and reimbursement decision processes of VAMs should allow for ex-ante non-RCT evidence for certain domains. Alternatively, relying on ex-post evidence agreements—such as outcome guarantee or coverage with evidence development—can also reduce decision uncertainty.The core evaluation framework for VAMs could trigger changes in the existing pricing, reimbursement and procurement practices by improving the appraisal of the added value created by incremental innovation. Pharmaceutical research and development (R&D) of new molecules entails substantial investment with usually over 10 years until patients can access the new products , 3. The Well-established medicines are pharmaceuticals with an active ingredient that has been used for several years and their efficacy and safety is already well known . IncremeAs the second part of this research, Report 2 discusses the key pharmaceutical policy implications of the proposed value assessment framework. The core evaluation framework is based on a systematic approach to facilitate the appraisal of differential value in a scientifically rigorous yet pragmatic way. Still, two important questions remain open. Firstly, more clarity is needed on whether the core evaluation framework can be transferred and adapted to heterogeneous health care financing systems. If reasonable solutions can be proposed for the framework adaptation in different jurisdictions—especially if best practices for the adaptation are shared—the willingness of decision-makers to use the value framework in their national pricing and reimbursement decisions may increase. Secondly, it should be explored whether the anticipated cost of evidence generation necessitated by the value framework takes into account the magnitude of claimed benefits for the health care system and the anticipated reward for the VAM developers. The objective of this review is to discuss different aspects related to these questions, mainly from the European perspective.Several countries have already introduced special evaluation criteria for special health technologies, such as orphan drugs, vaccines, end-of-life therapies, curative gene therapies or digital technologies. This trend indicates that a specific evaluation framework for a class of medical technologies can be politically attractive and is already happening in different jurisdictions.If policymakers in several countries are interested in facilitating the sustainability of incremental pharmaceutical innovation, they can consider adapting the core evaluation framework of VAMs proposed in Report 1 to their national pricing, reimbursement or procurement system. As there are significant differences in the pharmaceutical policy processes across European countries, three main decision-making contexts are considered below for incorporating the core evaluation framework of VAMs to national policies.Public payers in many countries apply policy tools to accelerate price competition of off-patent medicines by generic substitution or internal price referencing and select the more affordable generic or biosimilar medicines in the reimbursement or procurement system . Certain medicines, including VAMs, could be exempted from generic substitution and price referencing groups, or they can be integrated into the reimbursement and procurement system with a reasonable price premium (compared to the reference generic medicines) due to their added value. In such cases, the exemption or the price premium could be decided in a deliberative process based on the submitted evidence or arguments. Due to the deliberative nature of the process, often no explicit rules and criteria are determined upfront; hence decisions may not be replicable, especially for external stakeholders. A core evaluation framework, that is detailed in Report 1, can provide guidance on the rules of exemption from internal price referencing or the acceptability of a price premium in the reimbursement or procurement process for all stakeholders concerned by the deliberation, including the decision-makers, which can eventually improve the consistency and replicability of decisions in deliberative decision frameworks.The proposed core evaluation framework for VAMs can also be relevant in countries where cost-effectiveness analysis is mandated to justify the price premium of any medicine . In such decision contexts, traditionally, the ratio of incremental costs and incremental quality-adjusted life years (QALY) is compared to a willingness-to-pay threshold. As the traditional cost per QALY assessment has a limited focus on patient experience, societal benefits and other non-traditional value propositions, an augmented cost-effectiveness analysis might be considered . In an aThere is a growing interest in applying specific extended evaluation frameworks and multi-criteria decision analysis (MCDA) to support the priority setting, pricing, reimbursement and procurement decisions of special types of health technologies, including orphan medicines, off-patent medicines, vaccines, medical devices or intensive care for patients with severe infections –19. MCDAStill, in some countries, the separation of a new class of pharmaceutical products for policy decisions cannot be an attractive option from a political point of view. However, even in these countries, some domains of the core framework could be added to current “one size fits all” evaluation frameworks of medicines to make them more receptive to the benefits offered by VAMs. It is also expected that policymakers and health technology assessment (HTA) bodies will be more and more willing to consider non-RCT evidence or ex-post evidence generation techniques (described in the next chapter) for certain value claims of VAMs. Such an extension of general evaluation frameworks would be beneficial not only for VAMs but also for other special health technologies, such as personalized medicines, vaccines or medical devices.It is a fair expectation of policymakers, health care professionals and patients that the benefit of VAMs should be substantiated by robust scientific evidence. On the other hand, the evidence base of different health technologies is not equally strong for technology assessment before policy decisions. Although evaluators can hardly rely on evidence from double-blind, randomized controlled trials (RCTs) in the evaluation of medical devices, public health interventions or even orphan drugs, these technologies and interventions are still continuously incorporated into the health care systems with public reimbursement –27.The situation is quite similar to the incremental innovation of established medicines. Firstly, VAM developers compose regulatory submissions by relying on the substantial existing knowledge about the safety and efficacy of the originator medicine and—depending on the claimed benefit— generate additional evidence that can support their application for reimbursement. Phase 2 and 3 RCTs are not necessarily required for the market authorization of several VAM types. Even when RCTs are required, due to the known safety profiles of established medicines in other patient populations, the follow-up period or the sample size can be reduced. Therefore, the strength of regulatory data for VAMs may not be comparable to the data of originator medicines. Consequently, the evidence expectations for reimbursement decisions on VAMs should be cognizant of the degree of innovation, the level of risk for the payers, and the feasibility of generating the expected level of evidence. Furthermore, evidence requirements for VAMs should be assessed on a case-by-case basis. Ideally, the cost of evidence generation should be proportionate to the magnitude of claimed benefits, anticipated risks and the expected price premium. The joint relative effectiveness assessment process (facilitated by EUnetHTA) provides an opportunity to judge the value also of VAMs in high priority diseases at the European level. These joint assessment processes may reduce the heterogeneity of quantifying expected benefits and reduce parallel efforts; generating evidence for a health technology concurrently in several countries –30.Secondly, certain benefits, such as improved adherence, reduced resource utilization and treatment costs, can only be measured in the real-world setting and not in protocol-driven clinical trials. Compared to the cost of prospective RCTs, confirmatory real-world evidence for prescription drugs with a sufficient sample size could be collected at relatively low costs in observational studies, patient registries, or payers’ databases, typically ex-post, after the positive reimbursement decision . This mePerformance-based risk-sharing approaches with ex-post (after policy decisions) real-world data collection can provide a solution to the problem of premature scientific evidence in areas with a high unmet medical need . If the The complexity of evidence generation and acceptability of evidence  for decision-makers are different for each domain in the core evaluation framework of VAMs. Table Currently, there are limited incentives for pharmaceutical companies to invest in further improving health technologies after patent expiry, despite the known targets for potential improvement , minimal chances for unexpected serious adverse events and consequently lower development costs. As a consequence, the evidence base of non-patented medicines—which represent the vast majority of the therapeutic armamentarium—hardly improves over time. Although international policymakers and regulators can make the motion for necessary changes , this unfavorable trend can hardly be solved without policy actions and better coordination at a national level in most countries .The first option may be to develop predictable and transparent mechanisms to implement value-based price differential for VAMs relative to their generic comparators. Alternatively, VAMs may be exempted from certain policy solutions to facilitate generic price competition in those countries where this is not a common practice yet. We hope that the publication of the core evaluation framework proposed in Report 1 could be an important trigger for changes in the existing pricing, reimbursement and procurement practices by proposing an explicit list of potential domains for determining the added value of incremental innovation.A typical example for the inappropriate policy environment is that repositioned medicines in their new indications or extended patient populations may be subject to internal price referencing or generic substitution at the pharmacy level. Even if this is not officially allowed, but in the real-world the exemption rule is not enforced to prevent the off-label use of generic medicines in new indications or patient populations, there is limited incentive for the private investment in drug repurposing. Therefore, the exemption rule should be supported by further regulatory and technical solutions or specific pathways to prevent the free-ridership of other manufacturers, who keep the development cost of their generic medicines at the minimum level.As an alternative to private investment by VAM manufacturers, public investment or public-private partnership could also be utilized to test off-patent medicines in new indications or patient populations, as exemplified by recent trials of hydroxychloroquine to prevent or treat the SARS-CoV‐2 (or COVID-19) infection –37. HoweIncreased investment into the development of VAMs may positively impact different stakeholders, primarily patients, but also health care systems and manufacturers. However, changing the landscape of pharmaceutical R&D processes, specifically VAM regulations and policies, should be continuously monitored to prevent any negative outcomes. Special attention should be given to situations where market competition is limited and market concentration exists prior to or upon the introduction of VAMs to the market. The objective of such surveillance mechanisms could prevent issues, such as unjustified price increases or potential shortages of medicines.The core evaluation framework for VAMs (see Report 1) can only deploy its full impact if it is adapted and adopted to the national pricing, reimbursement or tendering systems in several countries in the upcoming years. Similarly to the EUnetHTA HTA Core Model, the national derivate of the core VAM evaluation framework can differ from country to country –30. Out The core evaluation framework gives a message to VAM developers that it is not enough to complete the minimal technical and regulatory steps of repositioning, reformulating or combining established medicines. They should also consider how to facilitate the policy-relevant value judgment on their medicines by ex-ante  or ex-post  evidence generation. In other words, the complexity of data collection should not be an excuse to approach payers or HTA bodies without a sound evidence base for the differential value .On the other hand, authors feel that further research is needed to clarify the complexity, feasibility and costs of evidence generation in particular value domains. The initial overview presented in Table Implementation of the core evaluation framework has multiple policy implications. The national adaptation of the framework across countries can reduce the heterogeneity of pricing, reimbursement or procurement decision-making practices related to VAMs on a broader international level. The framework may guide manufacturers on evidence requirements of VAMs, which eventually can facilitate the global evidence generation strategy for VAMs from their early development phase through to post marketing surveillance. Overall, improved predictability, transparency, consistency and reduced heterogeneity of decision-making could contribute to a more attractive and predictable business model for investing in VAMs and finally, resulting in the availability of more patient-centered and affordable medicines on the market.


A recent systematic review, which used the GRADE methodology, concluded that there is strong evidence for two gene-diet associations related to omega-3 and plasma triglyceride (TG) responses. Systematic reviews can be used to inform the development of clinical practice guidelines (CPGs).To provide guidance for clinical practice related to genetic testing for evaluating responsiveness to dietary/supplemental omega-3s and their impact on plasma lipids/lipoproteins/apolipoproteins.Using the results of the abovementioned systematic review, the first CPGs in nutrigenetics were developed using the established GRADE methodology and AGREE II approach.APOE-E4 carriers  and TG changes in response to the omega-3 fatty acids eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) as well as a 31-SNP nutrigenetic risk score and TG changes in response to EPA+DHA among adults with overweight/obesity. Ethical and regulatory implications must be considered when providing APOE nutrigenetic tests given the well-established link between APOE genetic variation and Alzheimer's Disease.Three clinical practice recommendations were developed. Most gene-diet associations identified in the literature lack adequate scientific and clinical validity to warrant consideration for implementing in a practice setting. However, two gene-diet associations with strong evidence  can be considered for implementation into clinical practice in certain cases: male Most of the evidence in this area is not ready for implementation into clinical practice primarily due to low scientific validity . However, the first CPGs in nutrigenetics have been developed for two nutrigenetic associations with strong scientific validity, related to dietary/supplemental omega-3 and TG responses. Genetic testing for personalized nutrition has been available for several years to the general public through direct-to-consumer services and healthcare professionals (HCPs). This can be referred to as nutrigenetics—the study of the influence of genetic variability and dietary/supplemental intake on subsequent health outcomes . There iAPOE  genetic variants in men, and TG responsiveness to EPA+DHA based on a 31-single nucleotide polymorphism (SNP) nutrigenetic risk score (nutri-GRS)  instrument was established to help guide comprehensive CPG development. A more recent iteration entitled AGREE II has been published  and usedThe specific objective of this study is to provide guidance for clinical practice and/or recommendations for future research related to genetic variation, dietary/supplemental omega-3 and plasma lipids/lipoproteins/apolipoproteins using the established GRADE methodology and AGREE II approach , 13–15. CPGs were developed by following the steps outlined in the GRADE Series' guideline on moving from evidence to recommendations –15 as weAPOE-related recommendations; specifying EPA+DHA for the nutri-GRS related recommendations; and clarifying that ALA has not been shown to have beneficial effects on TG levels.All relevant components of AGREE II were included in the CPG development . The fouAdherence to these CPGs can be monitored/evaluated as needed by conducting research assessing the proportion of healthcare professionals (HCPs) and companies abiding by the recommendations presented herein for their nutrigenetic tests. As new evidence emerges, these CPGs should be updated, using the same methodology.APOE  genetic variants in men   –24, and oderate) , 26. It OE rs42938, rs7412OE rs42938, rs7412Trade-offs between desirable and undesirable consequences of alternative TG management strategies (nutrigenetic intervention vs. other population-based strategies for TG management), as well as risks and benefits of omega-3 consumption and nutrigenetic testing were considered herein.trans fatty acids, and/or increasing physical activity  to reduce TG was deemed to be “important not critical” using the GRADE terminology .The information described in this section was used primarily to determine whether a weak/conditional (level 2) or strong (level 1) recommendation would be made in the present CPGs, as well as the potential caveats of these recommendation(s). Values and preferences of the target population  as well as HCPs were assessed through a literature review, which overall indicated that there is substantial interest globally in genetic testing for personalized nutrition –49. ConsAPOE SNPs. In other cases, a patient may be looking to complete genetic testing for these specific SNPs, and the feasibility of this will depend on what is offered by genetic testing laboratories and companies. With CPG development, the hope/goal is for companies to use the CPGs to develop evidence-based tests that can be offered to patients. Other additional resources beyond standard nutrigenetic care would include the initial investment of time required for the HCP to learn and understand the ethical and regulatory implications of APOE testing in their specific setting.The panel deemed it important to consider resource use for the present recommendations (in determining strength and direction), although this is considered optional in the GRADE approach . ResourcAn “Evidence to recommendations framework”  is proviRecommendation 1: The expert panel conditionally recommends that in male patients , nutrigenetic testing for TG responsiveness to EPA and/or DHA omega-3s can be based on genetic testing of APOE SNPs . Adult males with the APOE-E3/E4 or E4/E4 genotype appear to be most likely to experience significant TG reductions in response to 0.7–3.0 g/day EPA and/or DHA; higher dosages may have greater TG lowering effects (APOE-E3/E4 or E4/E4 genotype. Maximum EPA+DHA dosage regulations may vary depending on location therefore the HCP must take their location-specific regulations into consideration when deciding on the appropriate dose for the patient. effects . It shouAPOE genetic variations and Alzheimer's Disease (APOE (rs429358 and rs7412) as it relates to plasma TG responsiveness to EPA and/or DHA, and HCPs offering such tests to patients must comply with the regulations relevant to their territory of practice, while also considering any ethical and legal implications of this test. Research laboratories testing these SNPs must work with their institutional research ethics board to determine how to proceed with APOE testing. How to best proceed with this test in an industry, clinical or research setting will be context specific. Consent for APOE genotyping should always be obtained from patients prior to completing genotyping, as they would incidentally also be learning about other disease risks, including Alzheimer's disease. Disclosure of results to patients and referral to appropriate HCPs such as genetic counselors and medical doctors for Alzheimer's disease risk counseling may be warranted if it is in accordance with the consent form signed by the patient. Thus, nutrition professionals (or company offering DTC testing) must be aware of available referral sources  prior to offering this test. This recommendation is also conditional on any context-specific policies and regulations related to APOE genetic testing, as well as the patient's consent to undergo APOE testing and disclosure of the results related to Alzheimer's disease risk (or not).Given the link between these  Disease , CompaniRecommendation 2: The expert panel further conditionally recommends that the nutri-GRS developed by Vallée Marcotte et al. —it does not imply that the evidence to support the test is weak, which is a common misconception , related to a 31-SNP nutri-GRS and nception . In factnception .These CPGs can be used by HCPs and industry alike to help promote evidence-based practice in personalized nutrition. Industry should use these CPGs to inform the nutrigenetic tests and omega-3 recommendations included in their reports. The CPGs can further be used by HCPs in cases where a patient brings results from a direct-to-consumer report to their appointment; HCPs can then verify the validity of any information included in the report related to omega-3s and lipid/lipoprotein/apolipoprotein outcomes. HCPs and consumers can further cross-reference these CPGs with existing nutrigenetic tests related to omega-3s and plasma lipids/lipoproteins/apolipoproteins to determine those that are evidence-based (and those that are not), and the caveats of those that are ready for implementation into practice. Decision aids can be useful to guide clinical practice for HCPs , and canAPOE-E4 carriers is estimated to range from 7 to 31%, with rates variable depending on ethnicity (APOE-E4 carriers compared to other ethnicities (around 7%), such as individuals from Norway who have one of the highest frequencies (around 31%)  . Based ound 31%) . Notablyund 31%) –64, so tAPOE nutrigenetic testing described herein is generalizable to adult males only. Therefore, this test is not considered to be scientifically valid in females at this time. Similarly, the 31-SNP nutri-GRS is generalizable to adults with overweight or obesity and is therefore not yet applicable to other subsets of the population. Future research should thus include sex-stratified analyses, focus on broader target populations, and should further prioritize interventional study designs especially randomized controlled trials given that these study designs tend to lead to higher levels of evidence  (#430907), NUTRISS, and INAF. IR holds a Junior 2 research Scholar from the Fonds de Recherche du Québec—Santé (FRQ-S). M-CV holds a Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health. None of the funders played a role in the content of these CPGs.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


About 8% of all children and adolescents worldwide are affected by chronic diseases. Managing chronic conditions requires pediatric patients to be health literate. The purpose of this review is to examine the existing evidence on the links between health literacy and its outcomes proposed by the model by Sørensen et al. in chronically ill pediatric patients. Four electronic databases  were searched to identify pertinent articles published up to November 2021. The search was conducted independently by two researchers and restricted to observational studies. Of 11,137 initial results, 11 articles met eligibility criteria. Overall, 6 studies identified a significant association between health literacy and one of the considered outcomes. Regarding health behavior, none of the studies on adherence found significant associations with health literacy. The results in terms of health service use were inconclusive. Regarding health outcomes, health literacy did not affect most physiological parameters, but it significantly improved health-related quality of life. Overall, evidence remains inconclusive but suggests that health literacy is associated with self-efficacy, health-related quality of life, and health service use in pediatric patients. Further research should be undertaken to strengthen the evidence. Since the last century, the epidemiology of relevant pediatric diseases has changed significantly . While iIt has been stressed that in order to prevent adverse long-term effects, pediatric patients themselves need to take an active role alongside their caregiver’s responsibility. This becomes increasingly important in the course of adolescence and becomes indispensable in the context of transition. Transition readiness is defined as “the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented health care systems” . To streIn recent years, a growing number of studies has established a link between adult health literacy and the above-mentioned conceptual model. In various adult populations, a low level of health literacy is associated with poorer health outcomes and health behaviors, such as disease management skills or medication adherence ,26,27,28While the available evidence on health literacy in the adult population supports a link between health literacy and diverse outcomes , this maThe reporting of this review was conducted in accordance with the PRISMA  statement .pubmedThe literature search was performed in four electronic databases including PubMed, CINAHL, PsycINFO, and Scopus, from inception to November 2021. To update the results prior to publication, the search strategy was applied once more for evidence published between July and November 2021. Furthermore, reference lists of included publications were screened for additional relevant studies. The algorithm for the database screening process was generated by connecting particular search terms. Search terms were combined with Boolean operators (AND/OR). Search strategies were developed according to the specific requirements of the databases: AND ) CINAHL“health literacy” AND (adolescen* OR child* OR infant* OR juvenil* OR kids* OR paediat* OR pediat* OR school* OR student* OR teen* OR youth*)PsycINFO AND (“adolescent” OR child* OR “minors” OR pediat* OR paediat* OR “puberty” OR school* OR student* OR boy* OR girl* OR infant* OR juvenil* OR kids* OR teenage* OR kindergar* OR teen* OR youth*)Scopus AND (“adolescent” OR child* OR “minors” OR pediat* OR paediat* OR “puberty” OR school* OR student* OR boy* OR girl* OR infant* OR juvenil* OR kids* OR teenage* OR kindergar* OR teen* OR youth*)As outlined above, we focused on observational studies only. Studies were regarded as eligible if they investigated associations between health literacy and any of the eight outcome categories defined by Sørensen et al. . The outExtracted records were exported to reference management software. After removing duplicates, study selection was performed in three steps. First, articles were systematically selected by their titles based on inclusion criteria. Second, abstracts were screened and either included or excluded for the next screening step. Third, full texts of the remaining scientific publications were reviewed to determine whether they could be included. Two researchers independently conducted each screening step. A consensus meeting was undertaken at the end of each screening step to discuss discordances concerning the inclusion of studies. For methodological quality assessment, the Downs and Black checklist for observational studies and RCTs was applied . The tooAcross all electronic databases, the search yielded 11,137 results. After removing 5171 duplicates, 5966 studies remained for the screening process. In the first screening step, 5769 were excluded. Abstract screening of the remaining 197 studies excluded all but 48 studies. A final assessment was undertaken by screening 48 full texts. Ultimately, 11 publications met the eligibility criteria and were included for further analysis . The addThe majority of studies (7 out of 11) were cross-sectional studies. All articles were published between 2011 and 2020  in EngliQuality scores according to the checklist by Downs and Black  ranged fA total of seven standardized instruments on health literacy were used within the included studies. The most common tools were the Test of Functional Health Literacy in Adults (TOFHLA) ,62 . None of the other four studies considering physiological parameters  found a significant association with health literacy. Three studies focused on morbidity as an outcome. They found no correlation between asthma morbidity and health literacy. One study revealed that asthma patients with higher levels of health literacy reported higher frequencies of symptom days and higher rates of symptom bother. Another study identified a lower need for antibiotics in CF patients with high health literacy levels. In terms of effects on HRQoL, both studies showed significant associations between health literacy and HRQoL: One in a population of asthma patients, the other in CF patients. According to the longitudinal study carried out by Beukema et al. , poor heThis review summarizes the published evidence on the association between health literacy and outcomes from the eight outcome categories by Sørensen et al. in pediatric patients with chronic diseases. Overall, studies provided information on four of these outcome categories, specifically health behavior, health service use, health outcomes, and empowerment. To our knowledge, this is the first systematic review on health literacy and its outcomes in chronically ill pediatric patients. While for adult populations, ample evidence is available, largely confirming associations with outcomes, a very limited number of studies was found in pediatric settings. The small number of 11 eligible studies on this topic and the partly inconsistent results reflect a lack of evidence in this field. All in all, this review found that only about half of the studies included established significant associations between health literacy and health behavior, health care use, health outcomes, and empowerment in pediatric patients. However, consistent with previous research on parental health literacy in pediatric populations , our resRegarding health behavior, an association between health literacy and self-management was found in only one of three studies. None of the studies on adherence found a significant impact of health literacy in pediatric patients. This is in line with previous studies in adult populations, which did not show strong evidence with regard to health literacy and treatment adherence ,71. ThisHealth literacy showed significant associations with health service use in two of five studies. Murphy et al.  identifiOverall, studies on associations between health literacy and health outcomes, including physiological parameters, morbidity, and HRQoL, showed mixed results. Contrary to findings on the influence of parental health literacy on, for example, child blood glucose levels ,43, no sOnly two of three studies found an association with self-efficacy. A reason for these less conclusive results compared to adult populations may be the influence of puberty on levels of self-efficacy and self-management due to reduced motivation and reduced overall self-efficacy .Although we cannot identify significant associations between health literacy and some of the considered outcome measures, none of the study results suggest an adverse correlation. Moreover, significant results tended to be found in studies with larger sample sizes rather than those with smaller ones, indicating a potential lack of statistical power in some studies. Overall, four of five studies with more than 100 participants show significant results in terms of at least one considered outcome. Four of the five studies that did not identify any association are the ones with the smallest sample sizes. Overall, the identified studies used a large variety of health literacy instruments, of which only some were designed for or validated in pediatric populations ,79, specThe results need to be considered in light of the strengths and limitations of the study. First, our literature search term was extensive in terms of the outcomes observed. Hence, the studies included are quite heterogenous in terms of diseases and outcomes examined. No meta-analysis was undertaken due to the insufficient number of studies measuring similar outcomes in comparable populations. Thus, generalisability remains debatable. However, our aim was to provide a comprehensive overview of this still-developing field of research. Due to the broad search term, we hope to have been able to include all available evidence on the impact of health literacy on outcomes. Considering that we searched four large databases that yielded 11,137 results, we assume that we were able to include the relevant studies. Second, no suitable tool for evaluating exclusively observational studies was available. Hence, we had to choose a mixed tool for RCTs and observational studies whose design made it impossible for any of the included studies to reach full scores. Nevertheless, this validated tool allowed examining diverse aspects related to study quality. Third, exclusively observational studies were examined. This entailed an overall reduced study quality because observational studies are of moderate evidence level in general. The majority of the studies were cross-sectional studies, which looked at the current state of patients rather than their disease process. Any long-term benefits from a high level of health literacy in childhood and adolescence were therefore neglected. Nevertheless, it was important to undertake this selection because we wanted to focus on the fundamental association between health literacy and outcomes in pediatric samples. The evidence found can then contribute to the design of interventions to improve health literacy in either parents or patients themselves or both. The present review highlights the fact that health literacy may play a considerable role in health behavior, health service use, and health outcomes, including in pediatric patients with chronic diseases. However, it emphasises that the current state of research is limited, and future research is needed to better understand the association between health literacy and outcomes in pediatric patients with chronic diseases. The included studies partly lacked methodological quality, warranting future studies to determine appropriate study designs and measurement instruments. In general, future studies with longitudinal designs are needed. A precondition for valid results of those studies is the implementation of reliable health literacy tools validated for underage populations. While we are aware of the challenges associated with survey research in young children, future studies should moreover focus on age-related differences concerning health literacy, including in young children. Moreover, the impact of parental health literacy on child health literacy should be examined. Additionally, key dimensions in terms of healthy literacy in children and adolescents have to be identified in order to shape and adjust the content of educational programs. Several interventional studies have been recently undertaken to improve children´s health literacy and suggest promising effects on health outcomes ,46,82. Most of the included studies used a cross-sectional design. Accordingly, complication rates, long-term prognosis, as well as psychosocial and cognitive long-term development were underrepresented outcomes. To build a profound evidence base on health literacy in pediatric patients with chronic diseases, these aspects need to be considered, requiring longitudinal studies.All in all, the small number of identified studies in our review reflects the fact that few existing studies have focused on the children´s perspective. In contrast, the wider literature outside the scope of this review shows that caregivers and parents have frequently served as research subjects . Prior rRecapitulating the research process, it is striking that the studies included provided information on only four of eight possible outcome categories. The influence of health literacy on sustainability, equity, participation, and health costs were therefore neglected in this review. One reason for this may be the aim of the study, focusing on the individual perspective of children and adolescents. However, future research should contemplate the remaining aspects in order to depict health literacy comprehensively. Furthermore, in order to embed health literacy into a larger context, future research should examine the impact of environmental factors on adolescents´ health literacy. In consideration of all these contextual factors, research may be able to provide politics with recommendations on how to create an appropriate setting in which children and adolescents with chronic conditions can develop unrestrained.


Hundreds of businesses across the United States offer direct-to-consumer stem-cell-based interventions that have not been approved by the Food and Drug Administration. Here, we characterize the types of evidence used on the websites of 59 stem cell businesses in the Southwest United States to market their services. We identify over a dozen forms of evidence, noting that businesses are less likely to rely on “gold-standard” scientific evidence, like randomized clinical trials, and instead draw substantially on forms of evidence that we identify as being “ambiguous.” Ambiguous evidence has some scientific or medical basis, but its interpretation is highly context-dependent. These findings highlight the interpretive responsibility placed on prospective patients. We identify actions for regulators and professional societies to assist with evaluating evidence, but caution that focusing on the (in)validity of particular evidence types is unlikely to eliminate demand for stem-cell-based treatments in this complex marketplace. •We characterize the evidence used by 59 stem cell businesses in the Southwest United States•We identify that clinics rely on scientifically and medically “ambiguous” evidence•Ambiguous evidence places interpretive responsibility on prospective patients•We offer suggestions to help prospective patients navigate this complex landscape In this article, Frow and colleagues characterize the evidence used by 59 direct-to-consumer stem cell businesses in the Southwest United States. Their analysis identifies the reliance of these businesses on scientifically and medically “ambiguous” information: information that has some scientific or medical basis, but its interpretation is highly context-dependent. These findings highlight the interpretive responsibility placed on prospective patients. There currently exist a large number of US clinics offering stem-cell-based interventions (SCBIs) for many different medical conditions. Researchers have been tracking this marketplace, publishing studies that characterize these clinics and their care providers . ScientiSpecifically, we extend an earlier characterization of stem cell clinics in the Southwest United States  to preseBusinesses offering SCBIs use many forms of evidence in marketing their services. In characterizing 59 stem cell businesses in the Southwest United States, we identified and tabulated the frequency of 13 different forms of evidence , looselyAs indicated in clinicaltrials.gov and no results were available on the clinic websites.Direct-to-consumer stem cell businesses invoked clinical data in multiple ways on their websites. Registered clinical trials were mentioned by four of the 59 businesses. Three businesses mentioned being actively involved in active clinical trials, and the fourth provided a link to a published clinical trial they had not been involved with. A further five businesses mentioned clinical trials, but these had not been formally registered with A quarter of businesses  provided some non-peer-reviewed clinical data on their websites, for example mentioning the number of patients they had treated and/or referring to aggregated patient outcome data. Half of these businesses (n = 7 of 14) were associated with one of the three main direct-to-consumer SCBI franchises in the United States .A more common approach to presenting information about clinical outcomes of SCBIs was in the form of patient testimonials , either as written quotations or video testimonials from individuals presenting themselves as satisfied patients. These invariably described positive treatment outcomes and/or offered glowing reports of the care provider and treatment process. A smaller number of businesses  mentioned celebrity figures (often athletes) who had pursued SCBIs; little clinical information was typically provided in these instances, and outcomes were rarely mentioned.https://beallslist.net/).Of the 59 businesses characterized, 21 listed specific, peer-reviewed scientific journal articles on their websites as evidence in support of SCBIs. These 21 businesses cited a total of 261 journal articles published in 170 different journals. Approximately 10% (n = 27) of the articles were published in leading stem cell and scientific journals  offered a commentary or summary of the article findings; the rest provided a citation but did not offer any interpretation of the research findings for prospective patients. Further analysis revealed an ambiguous relationship between the research papers cited and the specific treatments on offer at the clinic citing the paper A. We evaA further 75% of the articles cited (n = 195) did focus on clinical applications of stem cells, but the findings presented did not lend direct support for the specific interventions marketed by the business citing them. We categorized this set of papers as offering “ambiguous” evidence with respect to the services offered by the clinic B. The reStem cell businesses typically listed the medical qualifications of their care providers , three by the American Osteopathic Association (AOA), and the remaining 18 are independent medical boards . NotablySimilar heterogeneity was observed with respect to the professional associations listed by care providers  and S4. Just over half of the stem cell businesses mentioned the Food and Drug Administration (FDA) on their websites (n = 33). Mention of the FDA was more prevalent on the websites of sole-focus businesses  than main-focus ones  A. SimilaMentions of the FDA were not uniformly about clarifying the unregulated status of SCBIs B. For soOur study of direct-to-consumer stem cell businesses in the Southwest United States offers detailed insight into the forms of evidence mobilized by these clinics in promoting their services. In 2016, Turner and Knoepfler identified that the Southwest states captured approximately one-third of the SCBI marketplace in the United States, and included four of the seven “hot-spot” cities . While our study reports on a relatively small and geographically contained sample, we suggest the forms of evidence we identified are represented on the websites of direct-to-consumer stem cell clinics across the Southwest and the United States more generally, and that similar patterns in frequency of use are likely. Several of the forms of evidence we identify have also been observed on the websites of stem cell clinics in Australia and Japan , but witWe identify that stem cell businesses do not rely extensively on gold-standard forms of scientific evidence like randomized clinical trials, nor do they frequently cite patented products or procedures in support of their services. Rather, we observe that they rely extensively on forms of evidence that we describe as scientifically or medically ambiguous. By ambiguous evidence, we mean that there is a scientific or medical basis to the information being mobilized, but the interpretation of this evidence is highly context-dependent. Forms of ambiguous evidence mobilized by DTC clinics include (1) highlighting the training and expertise of the clinic care providers, (2) relying heavily on the use of scientific and technical jargon, (3) citing peer-reviewed scientific research papers, and (4) invoking patient testimonials. We use the term ambiguous to draw attention to the gray areas that are made visible when these forms of evidence are put under scrutiny by researchers and/or prospective consumers. This term also highlights the responsibility placed on individuals to interpret the evidence. We briefly discuss each of these gray areas below.Surveys show that the public views board certification as an important consideration when choosing a physician . HoweverTextbooks present authoritative views about the current state of knowledge in science and medicine, without necessarily relying on detailed referencing to support each fact or point. Critical to the authority of a textbook is the credibility of the author(s), with core textbooks in science and medicine typically authored by leading, trusted figures in their respective fields. The technical descriptions of stem cells, regenerative medicine, and treatment options detailed on almost all the DTC clinic websites analyzed in this study are written in “textbook” style, but it is not clear exactly who the authors are and what authority or expertise they bring to the table. As such, evaluating the accuracy of the claims made becomes more challenging.About one-third of the DTC stem cell clinics analyzed here cite one or more scientific research papers in support of the services they offer. These articles are published in peer-reviewed, credible scientific journals, and so at face value can be understood to present sound scientific findings. The key challenge for prospective patients is in interpreting whether the specific details of a cited study lend support for the particular treatment they are seeking. Our analysis identifies that this is very rarely the case, with fewer than 2% of the cited papers reporting clinical improvements in humans using exactly the same kind of same-day, minimally manipulated cell preparations offered by DTC clinics. Prospective patients are left to interpret the relevance of any differences between findings of published studies and the specific treatment they are considering.There is a long history in medicine of publishing case reports that focus on a single individual. Acknowledging that patient testimonials are clearly not equivalent to case reports, we nonetheless identify that there is some tolerance within the medical profession for sample sizes comprising one individual. A number of case reports have been published in recent years highlighting adverse effects faced by small numbers of individuals in response to unregulated SCBIs . The con•Are the qualifications of the care providers at the clinic appropriate for the specific treatment being sought? What is the history and credibility of a given medical board in certifying practitioners?•Do the research studies cited on the clinic’s website provide direct and unambiguous support for the specific treatment being sought?•Is the clinic explicit about the current regulatory status of experimental SCBIs?Direct-to-consumer stem cell businesses use many forms of evidence in marketing SCBIs online. The findings from this study highlight the significant interpretive responsibility placed on individuals when it comes to evaluating the credibility of a given business – they would ideally attend to the type of evidence and its specific content, as well as the context in which it is presented. For prospective patients seeking to do their due diligence, our analysis highlights the following questions:We see roles for professional societies and regulatory agencies in helping to navigate these questions. Medical boards can make explicit statements about their position with respect to SCBIs. In our sample, the American Board of Physical Medicine and Rehabilitation (ABPMR) stands out among the 30+ medical boards listed by clinic practitioners, with 25% of the board-certified practitioners citing certification by the ABPMR. Understanding whether the ABPMR offers explicit training in SCBIs or regenerative medicine, and what its position is with respect to such treatments, could be informative for prospective patients in evaluating the expertise of physicians certified by this board.Professional societies like the International Society for Stem Cell Research (ISSCR) can offer detailed guidance on factors to consider when reading scientific journal articles about stem cells; our analysis identifies several variables to include in such guidance. This list might also be relevant to the Federal Trade Commission (FTC) for their role in protecting consumers from deceptive marketing practices around SCBIs , as it pFinally, while these are steps that can be taken by the scientific and medical establishment to restrict deceptive practices and assist prospective patients with interpreting evidence, we note the limitations of such efforts for scientists, medical practitioners, and regulators concerned about the very existence of the direct-to-consumer SCBI marketplace. Making prospective patients aware of the “unscientific” or less scientifically legitimate nature of particular forms of evidence is unlikely to eliminate demand for SCBIs . Our empWe gathered publicly available material from the websites of stem cell businesses, focusing on forms of evidence used in marketing their services, as well as any statements regarding the regulatory status of the SCBIs on offer. Data collection was performed between late July and early September 2020. We began with the 169 businesses characterized in An overview of the data collected for each business is presented, in de-identified form, in E.K.F. and D.A.B. conceptualized the project. E.K.F. supervised the project. M.C., A.R., and E.K.F. were study investigators. M.C., A.R., and E.K.F. provided data curation and analysis.; M.C., A.R., and E.K.F. wrote the original draft. D.A.B and E.K.F. reviewed and edited the manuscript. M.C., A.R., and E.K.F. visualized the project.The authors declare no competing interests.