This study was carried out to gauge the prevalence of academic dishonesty among academics in Malaysian universities. A direct comparison was made between academics of healthcare and non-healthcare courses to note the difference in the level of academic integrity between the two groups. In addition, the predisposing factors and implications of academic dishonesty, as well as the different measures perceived to be effective at curbing this problem were also investigated.A cross-sectional study design with mixed qualitative and quantitative approaches was employed and data collection was carried out primarily using self-administered questionnaire.n = 74) of all respondents (n = 141) reported having personally encountered at least one case of academic dishonesty involving their peers. The results also revealed the significantly higher prevalence of various forms of academic misconduct among healthcare academics compared to their non-healthcare counterparts. Although respondents were generally conscious of the negative implications associated with academic dishonesty, more than half of all cases of misconduct were not reported due to the indifferent attitude among academics. Low levels of self-discipline and integrity were found to be the major factors leading to academic misdeeds and respondents opined that university managements should be more proactive in addressing this issue.Approximately half (52.5%, The outcome of this study should serve as a clarion call for all relevant stakeholders to start making immediate amends in order to improve the current state of affairs in academia. Academic integrity is the fundamental commitment that should be upheld by all academics in their meticulous bid to instil professional integrity among future workforce . The perThis study was carried out through a peer-reporting survey to gauge the prevalence of academic dishonesty among academics in Malaysian universities. The public generally holds high regards toward the healthcare professions according to the annual Gallup honesty/ethics poll , 15. ThiA cross-sectional design with mixed qualitative and quantitative approach was used to explore the prevalence of academic dishonesty among academics from numerous universities in Malaysia. In order to gain an insight into the climate of academic integrity within the academic fraternity in Malaysia, academics from both healthcare  and non-healthcare courses from six universities were recruited in this study.The study questionnaire was designed with reference to a previous study published by Archibong and co-workers which consisted of both closed-ended and open-ended questions . The queInformation pertaining to the prevalence of academic dishonesty was sought through asking respondents if they have ever heard or personally encountered any form of dishonest acts among their peers. Each form of academic misconduct was scored from 0 to 1, where 0 = have not heard/encountered; 0.5 = hearsay/rumours; 1 = direct personal encounter. The respondents were also asked to rate the perceived likelihood that academic dishonesty among academics might adversely affect the university. This was then scored from 0 to 3 where, 0 = Does not affect at all; 1 = Mildly affect; 2 = Moderately affect; 3 = Severely affect. The significance of different factors predisposing to the prevalence of academic misconduct among academics were rated by respondents and subsequently scored from 1 to 3 where, 1 = Low significance; 2 = Moderate significance; 3 = High significance.A total of 14 academics were recruited in a pilot study for questionnaire content validation and reliability testing. This was done to ensure that the questions were clear, easy to comprehend and sufficient to meet the study objectives. In addition, the questionnaire was also face validated and analyzed by two independent researchers. Reliability test was conducted using test-retest reliability method. Cohen’s kappa coefficient was used to determine the reliability of the questionnaire using SPSS and it yielded a value of 0.679 which reflected a substantial agreement of reliability .During the data collection phase, one of the researchers approached each participating university to gather the required information. The study questionnaire was sent to the coordinators at six participating universities, with a copy of the ethical approval letter, participant information sheets and consent forms. Convenience sampling was used to enrol all the eligible respondents during the study period. Due to the sensitive nature of this study, names of the participating institutions cannot be disclosed. Only the participants who have signed the ‘written consent form’ with a completed questionnaire were included in this study. Respondents were assured of their anonymity and data confidentiality to elicit honest response. They were informed that their participation was voluntary and completion of the questionnaire was optional to protect the respondents’ right to privacy. To further ensure confidentiality, only selected researchers in the team have access to the collected data.t-test and/or one-way analysis of variance (ANOVA), followed by post hoc analyses using Least Statistical Difference (LSD).Both descriptive and inferential data analyses were carried out using Statistical Package for Social Sciences, SPSS® version 18 with 0.05 as the level of significance. Descriptive statistics were used to analyse frequency, percentage, mean, percentile, range and standard deviation. Independent student Of over 1000 staff approached, only 141 academics from six Malaysian universities accepted and completed the study questionnaire, with an overall response rate of 13.5%. The demographics of respondents are summarized in Table n = 74, data not shown) of all respondents conceded to having personally encountered at least one case of academic misconduct throughout their career. The data showed that the most common form of impropriety among academics is absenteeism from work (average score = 0.45) with its prevalence being significantly higher than all other forms of misconducts (p < 0.005). Other incidences of misconduct identified include giving of publication authorship to non-contributor (average score = 0.37), academic plagiarism (average score = 0.33), covering up of student’s exam malpractice (score = 0.29), falsification of research data/finding (average score = 0.26), taking adjunct lectureship without permission from the university (average score = 0.19), leaking of exam questions (average score = 0.16), forcing students to buy books or other learning materials (average score = 0.16), falsifying exam records (average score = 0.1), writing student assignments for money (average score = 0.09) and accepting bribes to change student grades (average score = 0.05).The scores for all forms of academic misconducts reported by respondents are summarized in Fig. falsification of research data/finding (p = 0.009), leaking of exam questions (p = 0.002), writing student assignments for money (p = 0.004) and accepting bribes to change student grades (p = 0.005)  for monetary gain among non-healthcare academics compared to healthcare academics.The study also revealed the significantly higher prevalence of academic dishonesty among healthcare academics compared to their non-healthcare peers in the forms of 05) Fig. . MeanwhiAll other forms of academic dishonesty reported by healthcare academics and non-healthcare academics identified through the open-ended question were grouped according to common themes Table .Table 2TThis study also uncovered that 44.1 and 43.8% of all cases of misconduct encountered by healthcare and non-healthcare academics respectively, were not reported to the authority/management. The views of some of the participants which explains the factors influencing the decision in reporting academic dishonesty among peers:The boss always have [has] better say and approach to higher authority than juniors. As a result of which no juniors dare to complain. They just mold themselves and [are] bound to do unethical things.”“Nobody wants to be a whistle-blower, and the Asian culture makes it not socially acceptable to ruin a person’s ‘rice bowl’ [career] with reporting of an untoward incident.”“Its[it’s] none of my business”““Assumption that [it] is a normal and acceptable practice”Other reasons for the lack of misconduct reporting cited by the respondents through the open-ended question were grouped according to common themes Table .Table 3Tthe loss of trust and respect for the lecturers involved in academic dishonesty (average score = 2.69)  , followed by spurring students’ participation in academic misconduct (average score = 2.33) and spurring other lecturers to initiate and participate in academic misconduct (average score = 2.12).The most severe adverse implication was thought to be 69) Fig. . It is wlack of discipline/moral/ integrity (average score = 2.55), followed by desperation for promotion (average score = 2.34), excessive workload (average score = 2.28), lack of commitment (average score = 2.28), greed for money (average score = 2.24), lack of research skill (average score = 2.11), poor supervision by superior (average score = 2.00), wanting to be popular among students (average score = 1.82), lack of feedback from students (average score = 1.67) and pressure from students and parents (average score = 1.59). Figure lack of discipline/moral/ integrity as a more significant factor that predisposes to academic dishonesty compared to their non-healthcare counterparts (p = 0.0002). The perception towards other predisposing factors was comparable between both healthcare and non-healthcare academics.The most significant factor Fig.  was percOther factors contributing to the propensity of academic dishonesty as opined by several respondents (in the open-ended question and grouped according to common theme) were included in Table “In the absence of specific code/guidelines, lecturers may undertake activities that compromise good governance. It is also useful to know what the university’s philosophy is especially in areas where there are much (sic) ambiguities”“The code of ethics will serve as standards to foster mutual trust, to encourage free exchange of ideas as well as to advance the quest for knowledge by requiring intellectual honesty in teaching, learning and research”The various measures proposed by the respondents through the open-ended question were summarized according to common themes in Table The findings of this study corroborated the high prevalence of academic dishonesty among academics in universities previously reported by several media outlets , 12. ThiThe examples of other misconducts named by participants were often associated with compromised teaching quality such as unprofessional grading or giving undeserving marks to students; bending of rules for selected students or favouritism; misuse of research grant funding and; covering up of another academics’ misconduct. These behaviours were seen to be driven by the desire to gain favour from students, possibly in attempts to obtain a good assessment score as part of the academic’s performance evaluation.Despite being common knowledge, academic dishonesty is often not openly discussed/reported probably due to its sensitive nature . The lowSuffice to say, academics are well aware that their misdeeds cast a bad light not only on their own image and credibility as educators but also that of the universities; in addition to propagating the unwholesome culture of cheating in universities. The trust and respect vested on academics and graduates of these universities are also indirectly at stake . The awaThe findings unveiled low levels of academic integrity and/or the poor understanding of its principle among academic staff which is believed to have led to flawed ethical judgment among academics resulting in injudicious decisions at workplace. The higher awareness among healthcare academics that low levels of discipline/moral/integrity is the primary factor predisposing to dishonest acts appears paradoxical, given the significantly higher prevalence of numerous types of transgression reported among them compared to non-healthcare academics Fig. . This fiMore importantly, the general disregard for ethical obligations among academics was found to be driven-primarily by self-interest which calls for a more humanistic approach to address the possible root causes rather than deterrent policies in addressing such problems.The common cases of unscrupulous authorship exchange, academic plagiarism and falsification of research data on the other hand, also highlighted the dreadful ‘publish or perish’ phenomenon plaguing academia in the rat race for university global rankings , 20, 27.The suggestions provided by participants pointed towards the general sentiments that a more proactive role by the university management in administering university policies would aid in tackling academic dishonesty . This alProvide proper channel and procedures for anonymous reporting of academic dishonesty.Any enquiry towards alleged academic dishonesty should be transparent and the outcome made known to preserve institution’s integrity.Setting of realistic goals for career progression for academics to prevent resorting to unscrupulous means to achieve these goals.Transparent and strict enforcement of the code of ethics by an independent body – punishment should not be dependent on one’s rank.Only individuals with the right credentials and professional integrity should be appointed to leadership positions in order to lead by example.In this context, proper reporting channels should be made available to promote judicious reporting while investigation procedure and its outcome must be made transparent to restore the confidence of academics toward the system. There is also a dire need for impartial enforcement of policy whilst conferring protection upon whistle-blowers particularly if the perpetrator is a person of authority within the organization. More pertinently, only impeccably credentialed individuals with admirable integrity should hold leadership positions, making leadership by example a reality. The following is a summary of recommendations based on the various measures proposed by respondents:This research is the first of its kind, designed with the aim to compare the prevalence of academic dishonesty between academics of both healthcare and non-healthcare courses. Moreover, the use of mixed quantitative and qualitative approaches in this peer-reporting survey had elicited a more comprehensive ‘on-the-ground’ insight into the predisposing factors, implications as well as numerous proposed measures for tackling such issue. The sentiments shared by respondents would therefore be useful for universities in devising more effective and targeted interventions. It is worth noting that the data of this study may represent a lower estimate of the true prevalence given the lower-than-expected participation rates due to the sensitive questions being asked in the survey. Undoubtedly, a larger sample size with sampling centres across the country would provide a better reflection of academic dishonesty in Malaysia.The psychological barriers among academics which post hindrance to their voluntary participation in order to secure a higher response rate.The reasons underlying the higher prevalence of dishonesty among academics teaching healthcare courses compared to their counterparts in non-healthcare courses.The opinion among academics on what constitutes as practical procedures or relevant outlets for confidential reporting of academic misdeeds encountered.The perception among management of universities and academics regarding severity of misconducts among academics and perceived justifiable penalty towards those with reprimandable behavior.It would be interesting for future studies to address the following issues which would no doubt provide a clearer insight for devising remedial actions to counter academic dishonesty:The outcome of this research has reaffirmed the open secret pertaining to the dishonest acts among academics with the irony of them supposedly being role models for character and intellectual development among university students. Of greater concern is the overall higher prevalence of lapses in academic integrity among healthcare academics despite their highly esteemed professional background. In view of this, all institutions of higher learning should embody a clear definition of academic integrity in the university tenets and to ensure that its underlying core values are upheld at all times. Nevertheless, university policies must also be viewed as egalitarian and practical in order to foster compliance. Reference should be made to outcomes of existing studies and other exemplary guidelines in the drafting of institutional policies that can be relied on to promote transparency in addition to averting potential conflicts of interest in the academic fraternity. More importantly, university management should take heed of the feedback given by the academics such as those elicited by this study by taking immediate actions to address the issues.


Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity.N = 9), paediatric patients with chronic disorders (N = 10) and patients with SMA (N = 15).We developed a set of endurance tests using five methodological steps as recommended by the ‘COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). In this iterative process, data from multiple sources were triangulated including a scoping review of scientific literature, input from a scientific and clinical multidisciplinary expert panel and three pilot studies including healthy persons  contains supplementary material, which is available to authorized users. SMN1) gene , 1817, 1The first step in the development of a new outcome measure consisted of the operationalization of the theoretical construct in SMA. This included a clear definition of fatigability, a description of the target population and the purpose of the outcome measure and the composition of specific test criteria. The taxonomy for fatigue and fatigability as proposed by Kluger et al. was used as a starting point from which a construct for fatigability assessment in SMA was described. Fatigability was defined as the magnitude or rate of change in a performance criterion relative to a reference over a given time of task performance or measure of mechanical output . SeveralDuring the second step we combined the results from a scoping review on available measures for fatigability in patients with SMA with the experiences with fatigability testing by our research group.Trial.gov up to the first of October 2014. The following search strings was used:  OR “spinal muscular atrophy”[All Fields] OR ) OR ) AND (((Fatigability [All Fields] OR Endurance [All Fields]) OR Stamina [All Fields]) OR (“fatigue”[MeSH Terms] OR “fatigue”[All Fields])). At first, papers were selected that described the measurement of fatigability or endurance in patients with SMA. Secondly, outcome measures were assessed to what extent they complied with the definition and test criteria defined within this study. In the case that no suitable outcome measure were retrieved, the expert panel discussed in the first round table discussion whether other appropriate outcome measure were available that met the clinimetric requirements and could be validated for SMA.Given the fact that SMA has been associated with fatigability only recently, it was anticipated that a systematic review would not generate significantly more information than a scoping literature search. Peer-reviewed experimental articles written in English were retrieved from Pubmed and During the third step, questionnaires were taken from the pilot sample of patients with SMA to determine which activities of daily living (ADLs) provoked fatigability. In adults, the questionnaire by Straver et al. was used which was originally validated for peripheral nervous system disorders . A similDuring the fourth step, the expert panel discussed about the composition of the tests, taking into account the application setting  and the patient group, and selecting primary outcome parameters. For example, tests are usually shorter in clinical practise, due to time constraints .http://www.treat-nmd.eu/registry/310/) [SMN1 gene or a heterozygous SMN1 deletion in combination with a point mutation on the second SMN1 allele. In order to be eligible to participate in this study, a subject had to meet all of the following additional criteria: age 8–60 years; ability to follow test instructions and no exercise restrictions. Two patients with SMA declined participation due to frequent hospital visits in the recent past and fear of increased fatigue. Patient controls were recruited from a school for special education in Utrecht. Healthy controls were recruited from the University of Applied Sciences and the University Medical Center Utrecht. The outcome measures for fatigability were pilot-tested on ‘comprehensibility’ (‘Are test instructions to participants unambiguous and well understood?’) and ‘feasibility’  in three consecutive pilot samples of healthy controls (pilot sample 1), paediatric patients with chronic diseases (pilot sample 2) and patients with SMA (pilot sample 3). ‘Measurement completion rate’ was defined as the number of participants able to complete the test without premature discontinuation caused by motivational issues or a-specific physical complaints [Patients with SMA were recruited from the Dutch SMA registry (ry/310/) . This remplaints . ‘Acceptmplaints . Perceivmplaints . The thiContinuous performance of a prolonged task , 21:Intermitted submaximal exercise protocol which mimics activities such as walking or cycling in which fatigability develops over a longer periodContinuous maximal protocol which mimics activities such as lifting heavy objects or sprinting2)Comparing performance on a probe task before and immediately after prolonged performance of a separate fatigue inducing task .Fatigability is subdivided in ´physical fatigability’ and ‘cognitive fatigability’ which are measured in different ways , 24, 31.Fatigability is experienced by patients with SMA as the inability to perform prolonged repetitive tasks during activities of daily life. These complaints are reminiscent of those of patients with myasthenic syndromes, which are caused by reduced efficiency of neuromuscular junction . Moreoverepeated Nine Hole Peg Test (rNHPT) as a measure for fatigability of arm and hand function in patients with SMA. Given the promising results, the r9HPT was included in the assessment of potential outcome measures derived from the review. Recently, this study was published [The scoping review search performed on the 1st of October 2014 retrieved 109 records in Pubmed and no additional records in trial.gov. All records were screened on title and abstract. Seven papers were included describing 4 different methods to assess fatigability in SMA ) was chosen by the expert panel as the primary outcome measure of all three endurance tests (round table discussion 3). With the aim to eventually use the set of tests both in research and clinical practise time constraints in the latter had to be taken in account . To imprN = 1), Cerebral Palsy (N = 2), SMA (N = 2), Duchenne Muscular Dystrophy (N = 2), Spina Bifida (N = 1), Acquired Brain Injury (N = 1) and Spinal Cord Injury (N = 1)) to determine the feasibility of the endurance tests. All participants showed good comprehensibility and acceptability of the tests without any adverse events. Three children (SMA (n = 2), Spinal Cord Injury (n = 1) demonstrated a decreased time to limitation.Eight healthy adults and one adolescent  performed all three endurance tests. Respectively 30 and 44% of the subjects could not continue at an intensity level of 85% for at least 10 min during the ESWT and ESBBT. Early termination was primarily caused by subtle coordinative errors due to the high velocity at which the motor task was performed. Therefore, intensity level of 85% was not considered valid for the assessment of fatigability in patients with SMA. Assessment at a 65% intensity level was considered too easy. It was therefore decided to set the intensity level at 75% for all tests. Consecutively a second pilot study was performed in 10 children with neuromuscular diseases and other motor disabilities , type 3a (n = 5) and type 3b (n = 3) aged 10–49 and with a broad range in clinical severity  . Second, we decided that compensatory movements (e.g. leaning on the box during the performance of the box and block test) was no longer allowed. Materials and procedures for the set of endurance tests were described , we expect the endurance tests to be suitable for subjects aged 6 years and older for those being able to move around their dominant hand on their wheelchair table as minimal motor function. The additional burden and time consumption in the context of endurance tests as part of the already extensive trial assessments asks for a clear rationale about the efficacy in terms of function accompanied by the selection of the most appropriate tests. In order to be able to measure clinically relevant improvement in endurance, endurance tests that mimic long-term activities are required.In the current literature, the concept of fatigability and fatigue are often used interchangeably with different terms such as fatigue , fatigabWe decided to limit our search for existing outcome measures to a scoping review in SMA although a systematic review in the entire range of neuromuscular diseases could have generated other endurance measures. Based on experience by the expert panel and the specific characteristics of SMA regarding clinical variability and complaints of fatigability, it was anticipated that a time consuming systematic review would give very limited additional information as hardly any endurance testing has been developed in neuromuscular diseases. The involvement of patients in rare disease clinical trial design is increasingly becoming a priority . AlthougFatigability has emerged as an important dimension of physical impairment in patients with SMA. The development of a comprehensive set of endurance tests is a pivotal next step to facilitate intervention studies on fatigability and address this important complaint in patients with SMA. We developed a set of endurance tests for both non-ambulatory and ambulatory children and adults with SMA which meet predefined specific criteria to achieve three main objectives: 1) quantify endurance; 2) generate clinical relevant outcome parameters and; 3) cover a large part of the clinical spectrum of SMA. Reliability and construct validity need to be investigated in future studies.Additional file 1:Description of data: Description of studies about outcome measures considered for selection. (DOCX 17 kb)Description of outcome measures considered for selection. Additional file 2:Description of data: description of the materials and procedures needed to perform the endurance tests. (DOCX 334 kb)The Endurance Shuttle Tests: materials and procedures.


PTCA) alone causes severe injury of vascular endothelium. The damaged endothelium is intrinsically repaired by locally derived endothelial cells and by circulating endothelial progenitor cells from the blood, leading to re‐population of the denuded regions within several weeks to months. However, the process of re‐endothelialization is often incomplete or dysfunctional, promoting in‐stent thrombosis and restenosis. The molecular and biomechanical mechanisms that influence the process of re‐endothelialization in stented segments are incompletely understood. Once the endothelium is restored, endothelial function might still be impaired. Several strategies have been followed to improve endothelial function after coronary stenting. In this review, the effects of stenting on coronary endothelium are outlined and current and future strategies to improve endothelial function after stent deployment are discussed.Coronary artery stenting following balloon angioplasty represents the gold standard in revascularization of coronary artery stenoses. However, stent deployment as well as percutaneous transluminal coronary angioplasty ( However, both balloon angioplasty and stent implantation inevitably lead to near complete damage and loss of endothelial cells.The vascular endothelium acts as a barrier between the vessel wall and the blood flow. It regulates a variety of vessel functions, including the vascular tone and the passage of macromolecules such as lipoproteins.The healthy endothelium controls the tone and the proliferative state of the underlying vascular smooth muscle cells (VSMCs) by the production and release of bioactive substances as a response to changes in its physical, chemical, and humoral environment. Nitric oxide (NO) is known to be one of the most potent vasorelaxant and platelet‐inhibitory molecules and is produced by endothelial nitric oxide synthase (eNOS) from L‐arginine.2, thromboxan A2, and angiotensin II.In concert with NO, the significant role of the endothelium in maintaining the balance between vasoconstriction and vasodilatation is carried out by the production and secretion of vasoconstrictive substances such as endothelin, reactive oxygen species, endothelium‐derived cyclo‐oxygenase‐dependent vasoconstricting factor, prostaglandin H2 inhibits platelet activationThus, the functional vascular endothelium has a striking role in keeping the balance between blood coagulation and fibrinolysis and the vascular tone.Taken together, the initiation and progression of atherosclerosis is characterized by disturbances of normal endothelial functions.Intravascular processes such as balloon angioplasty and stent implantation inevitably cause severe vascular injury as well.c‐fos expression and drives neointimal formation and proliferation.On a macroscopic point of view the angioplasty immediately induces a change in the external size of the artery at the injured site, but the geometry of the vessel segment returns approximately to the 3‐D shape it had before the plaque intruded into the lumen.Another long‐term process has been identified as one major determinant of restenosis after balloon angioplasty in humans, known as constrictive vascular remodelling.The potential role of the endothelium in vascular remodelling after balloon injury has been discussed.2Arterial healing after denudation involves regrowth of the endothelium from remaining endothelial cells within the treated segment, from proximal and distal to the lesion as well as from side‐branch ostia.Delayed endothelial recovery has been identified as one of the major contributing factors of late stent thrombosis at autopsy.The biological factors controlling the re‐endothelialization process have not been completely elucidated. Both vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) represent growth factors for endothelial cells whereas FGF also has trophic effects on VSMCs. Balloon injury induces a release of FGF and an increased expression of FGF mRNA in endothelial cells and VSMCs.3Today, a broad variety of stents is available. There have been significant developments concerning the design of stent platforms as well as the stent coatings including novel polymers, polymer‐free stents and bioresorbable stents. The endothelial recovery after stent implantation is influenced significantly by the stent design. The protrusion of stent struts leads to perturbations in the local flow patterns notably to the development of small regions with disturbed shear stress between the stent struts.2, whereas areas of low shear rates adjacent to non‐streamlined struts are associated with inhibition of re‐endothelialization, potentially enabling procoagulant and pro‐inflammatory elements to accumulate which contribute to thrombus formation.In addition to the strut thickness also the shape of the struts influences re‐endothelialization process by changes in local vascular flow conditions. Non‐streamlined stent struts promote flow separation in the regions proximal and distal to the stent strut. High shear at the edges of the struts can activate platelets through the release of thromboxane A4Angioplasty and stent implantation cause denudation of the endothelium. The regeneration and regrowth of the denuded endothelium originates from the remaining endothelial cells and uninjured segments at the stent edges and from side‐branch ostia. However, vessels that need to undergo an interventional revascularization process usually are affected by atherosclerosis. The endothelium of atherosclerotic vessels is dysfunctional a priori, characterized by the impairment of vasomotion, disruption of the hemostatic balance, and a pro‐inflammatory milieu.Notably both the barrier integrity and the extent of dysfunctionality depend on the presence or absence of antiproliferative stent coverage. The majority of the currently available drug‐eluting stents release the mammalian target of rapamycin (mTOR) inhibitor sirolimus or one of its analogues . The mTOR pathway has an important role in modulating cell division in response to mitogenic stimuli by the control of protein synthesis mediated through formation of the TORC 1 and 2 complexes. Therapeutically the inhibition of mTOR and its target TORC inhibits the proliferation of smooth muscle cells (SMCs) in order to prevent restenosis. However, particularly in endothelial cells, TORC 1 and 2 components contribute to processes required for endothelial regrowth, function, and survival. TORC 1 influences the translation and activity of hypoxia‐inducible factor α, the most potent upregulator of VEGF, which is closely linked to the vascular healing process.The competence of the regenerated endothelium however seems to be better with newer‐generation than with first‐generation drug‐eluting stents. A comparison of the expression of eNOS following implantation of sirolimus‐, everolimus‐ and zotarolimus‐eluting stents in a rabbit model of atherosclerosis demonstrated a less‐delayed healing and greater expression of eNOS after deposition of a zotarolimus‐eluting stent.Intercellular junctions maintain the barrier integrity. Transmission electron microscopy of rabbit iliac arteries after implantation of DES demonstrated poor cell‐to‐cell contact and monocyte attachment.5Incomplete re‐endothelialization has been demonstrated particularly after the implantation of drug‐eluting stents due to the unselective antiproliferative effect of the drugs on both VSMCs and endothelial cells. It has been suggested that DES should ideally have a selective antiproliferative effect on VSMCs but be inert towards EC or better still promote their proliferation. The latter might be achieved by targeting factors influencing VSMC and EC growth. In this regard the impact of the administration of growth factors as well as the capture of EPCs have been investigated. In an effort to promote and accelerate the process of re‐endothelialization after stent implantation, novel stent designs have been developed, summarized as pro‐healing stents.Van Belle et al demonstrated a promotion of re‐endothelialization after stent implantation by local administration of VEGF in a rabbit iliac model.Another strategy to improve re‐endothelialization is followed by capturing EPCs from the blood flow. EPC capture has been attempted by coating stents with antibodies that target EPC markers such as anti‐CD133, anti‐VE‐cadherin (anti‐CD 144), and anti‐CD34.® (OrbusNeich) stent, coated with anti‐CD34 antibodies to capture EPCs, was the first device of its kind to be evaluated in humans. In preclinical porcine studies the early re‐endothelialization process was enhanced without affecting neointimal proliferation.® (OrbusNeich) stent combines CD34 antibody‐mediated EPC capturing on the luminal surface and a sirolimus‐eluting biodegradable polymer on abluminal surface. Reduced neointimal proliferation and accelerated re‐endothelialization were demonstrated in a porcine model.The GenousA combination of the administration of growth factors and the concept of EPC capture is followed by Song et al who performed in vitro studies with stainless metallic steel coated with VEGF and anti‐CD34 antibody.−/− mice an accelerated re‐endothelialization by supporting the adhesion and proliferation of EPCs, especially OECs, was detected, so RGD/CXCL1 coating of stents may help to diminish the risks of stent thrombosis and restenosis.Cyclic‐RGD (Arg‐Gly‐Asp)‐peptide has been identified as a recognition sequence for integrins and thus represents a binding motif specifically attracting endothelial progenitor cells.However, patients with cardiovascular diseases often have poor or dysfunctional EPCs. The treatment with statins has been associated with an increased number and survival of EPCs in patients with cardiovascular diseases.6Strategies enhancing the process of re‐endothelialization in stented coronary arteries do not necessarily result in reconstitution of all endothelial functions. To overcome the issue of incomplete and dysfunctional re‐endothelialization even immediately after denudation, Andukuri et al developed a bioinspired multifunctional nanomatrix mimicking the endothelial surface characteristics by containing cell‐adhesion ligands and NO‐donors.ACE inhibitors have been described as beneficial on intimal hyperplasia following balloon angioplasty.Exercise training is one of the key factors in primary and secondary prevention of cardiovascular diseases. Indolfi et al demonstrated that exercise training increases eNOS expression and activity resulting in an increased bioavailability of nitric oxide in the vascular wall of rats.® bioresorbable vascular scaffold (BVS) achieved a CE mark in 2011 as the first drug eluting fully bioresorbable scaffold. Imaging studies in porcine coronary arteries supported a restoration of cyclic pulsatility at the device site at 6 months after implantation.A promising strategy towards restoration of a normal vessel function is the development of fully bioresorbable scaffolds providing mechanical stability for a finite period after PCI and then being gradually resorbed leaving the vessel free of any foreign material. Today, there are several bioresorbable scaffolds at various stages of development, based on either metallic alloys or polymers. However, all bioresorbable scaffolds are characterized by thick stent struts when compared to second generation DES.7Catheter‐based interventional coronary revascularization procedures cause vascular injury including endothelial denudation. Compared to bare metal stents, drug‐eluting stents have achieved dramatically reduced restenosis rates. However, the antiproliferative drugs lack selectivity with respect to the targeted cell types. So not only the proliferation of VSMCs, underlying neointimal formation, is inhibited, but also the endothelial repair is compromised. Incomplete re‐endothelialization after implantation of stents has been identified as the primary cause of an increased risk of late and very late stent thrombosis. The regenerated endothelium in stented regions however is inadequate with regard to barrier, antithrombotic, and vasodilative functions, represented by poorly formed cell‐to‐cell junctions and reduced expression of antithrombotic molecules and eNOS. Additionally, stent‐induced disturbances of blood flow contribute to complex alterations in shear stress, resulting in increased thrombogenicity around the stent struts and impairment of re‐endothelialization. A complete regeneration of vascular endothelium prohibits neointimal thickening and hyperplasia and finally prevents restenosis. The long‐term health of the vessel wall depends on a successful restoration of a competent endothelium. Efforts have been made to promote re‐endothelialization and to improve endothelial functions after stent implantation by changes in stent design and coating. Future studies must address the long‐term safety of both new generations of DES and fully bioresorbable scaffolds aiming at the maintenance of a competent and functional endothelium in order to reduce stent thrombosis and restenosis rates.The authors confirm that there are no conflicts of interest.


The use of nipple‐sparing mastectomy (NSM) is increasing, despite unproven oncological safety in the therapeutic setting. The aim of this systematic review was to determine the safety and efficacy of NSM compared with skin‐sparing mastectomy (SSM).A literature search of all original studies including RCTs, cohort studies and case–control studies comparing women undergoing therapeutic NSM or SSM for breast cancer was undertaken. Primary outcomes were oncological outcomes; secondary outcomes were clinical, aesthetic, patient‐reported and quality‐of‐life outcomes. Data analysis was undertaken to explore the relationship between NSM and SSM, and preselected outcomes. Heterogeneity was assessed using the Cochrane tests.versus 3·3 per cent respectively; P = 0·45). NSM had a partial or complete nipple necrosis rate of 15·0 per cent, and a higher complication rate than SSM (22·6 versus 14·0 per cent respectively). The higher overall complication rate was due to the rate of nipple necrosis in the NSM group (15·0 per cent).A total of 690 articles were identified, of which 14 were included. There was no statistically significant difference in 5‐year disease‐free survival and mortality for NSM and SSM groups, where data were available. Local recurrence rates were also similar for NSM and SSM (3·9 In carefully selected cases, NSM is a viable choice for women with breast cancer who need to have a mastectomy. More research is needed to help further refine which surgical approaches to NSM optimize outcomes. Breast cancer is the most common cancer in the UK, accounting for 31 per cent of all new cancer cases and a lifetime incidence of one in eight in womenFrom its inception in 1894 until the 1960s, Halsted's radical mastectomy was the standard of care for patients. Later, the modified radical mastectomy (MRM) was described by Patey; this achieved a local recurrence rate of 10 per cent after 10 yearsThe principal reason why a surgeon may want to preserve a nipple is aesthetic, with studies reporting improved patient satisfaction and psychological benefitHistorically, mastectomy has included resection of both the NAC and the gland, the concern being that the NAC may harbour occult tumour cells. Indeed, large trials have reported the NAC to be involved in 5–12 per cent of casesTable S1, supporting information). Their quality is assessed in Table S2 (supporting information) using the validated assessment tool Assessment of Multiple Systematic Reviews (AMSTAR)Previous systematic reviewsTraditionally, progression to less radical or invasive surgical management of breast cancer has not produced worse outcomes, although this has coincided with extension of the use of systemic treatment and irradiation. Lanitis and colleagues' meta‐analysisFig. S1, supporting information).NSM is an active research front. A basic search using the database Scopus for ‘nipple‐sparing mastectomy’ reveals how research and interest in this area has increased over the past 21 years, from no indexed articles in 1995 to more than 80 in 2016  and published a prioriThis review was conducted in line with the recommendations specified in the Cochrane Handbook for intervention reviews version 5.1.0All comparative studies with levels of evidence 1–3, as defined by the Oxford Centre for Evidence‐Based MedicineWomen undergoing mastectomy for breast cancer were included. Men and transgender patients were excluded.The intervention of interest was NSM, which involves removal of all glandular breast tissue with preservation of the native skin envelope, IMC and nipple. The comparator was SSM, which involves the removal of all glandular breast tissue and the nipple, with preservation of the native skin envelope and IMC.Primary outcomes were overall survival and local recurrence rate in the follow‐up interval. Secondary outcomes were clinical complications (such as NAC or skin flap necrosis), haematoma, seroma, infection and readmission to hospital. Additional outcomes included aesthetic outcome as judged by the instrument used in the study, patient‐reported outcomes (such as patient satisfaction), and quality‐of‐life outcomes ).ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform.The following electronic databases were searched from inception to end of June 2017: MEDLINE; Embase; SciELO (Scientific Electronic Library Online); the Cochrane Library, including the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, DARE (Database of Abstracts of Reviews of Effect) and Cochrane Methodology Register; Health Technology Assessment Database; National Health Service Economic Evaluation Databases and Cochrane Groups; Table S3 (supporting information).The search was conducted by an information specialist experienced in systematic review, using appropriate keywords in the English language combined with Boolean logical operators. The search strategy for MEDLINE is shown in Searches were translated to the appropriate syntax of other databases, using free text and the relevant database thesaurus terms. The search was not limited by language.http://www.opengrey.eu). In addition, references of all included papers and previous systematic reviews were searched for relevant studies.Grey literature searches included a search of Open Grey . Duplicate articles were excluded. Articles were selected for inclusion via two steps. Titles and abstracts were screened by two researchers, and discrepancies were resolved through discussion; where agreement could not be reached, the article proceeded to the next stage. Next, the full texts of selected articles were downloaded and further assessed for inclusion by two researchers. When discrepancies could not be resolved through consensus, a senior author made the final decision on inclusion.Data extraction was performed independently by two teams of researchers. Each team screened all articles on the database. The work was split equally and distributed within each team. Any discrepancies that arose between teams proceeded to full‐text screening stage. If discrepancies persisted, they were resolved by consensus. Where required, data were reviewed by two senior authors. Data were extracted into a standardized Microsoft Excel® 2011 database. The data extraction template was first piloted by extracting a smaller sample of papers. This not only provided training to the extractors but also helped to ensure uniformity of extraction and identify issues early on, for example how to document aesthetic outcomes and quality of life. Authors were contacted to ascertain individual values for NSM and SSM where possible.Non‐randomized studies were scored according to the Cochrane risk‐of‐bias assessment tool ACROBAT‐NRSIFunnel plots were generated to determine whether there was a skew towards positive outcomes, thereby assessing for publication biasI2 statistic (I2 above 50 per cent), meta‐analysis was performed using a random‐effects model; otherwise a fixed‐effect model was usedNSM and SSM were compared. Using Review Manager 5.2.6 (RevMan)The intention was to perform an additional analysis to assess whether particular oncological profiles are associated with better outcome in NSM; however, this was not possible due to insufficient detail.Fig. A total of 690 articles were identified, of which 14 were included . Oncological profiles for the included studies can be found in Table S5 (supporting information). The mortality and local recurrence outcomes are shown in Table Table Table S6 (supporting information) summarizes complications across the NSM and SSM groups, and aesthetic and patient‐reported outcomes are shown in Table S7 (supporting information).Fig. a is a forest plot of mortality for NSM versus SSM; there was no statistically significant difference (P = 0·34). A random‐effects analysis was performed due to significant heterogeneity. Local recurrence for NSM versus SSM in shown in Fig. b; again, there was no significant difference (P = 0·45). A fixed‐effect model was used as the I2 statistic was 29 per cent.P = 0·45) or mortality outcomes (P = 0·34). The results of a systematic review are inevitably dependent on the quality of the studies included. In this context, it is possible that a difference does exist, but is obscured by selection bias and differences in duration of follow‐up. Nonetheless, it is unlikely to be large or clinically significant. NSM does have a higher complication rate of 22·6 per cent, compared with 14·0 per cent for SSM, largely due to a partial or complete nipple necrosis rate of 15·0 per cent, which is, by definition, avoided by sacrificing the nipple.Fourteen studies including 3015 breasts were included in this systematic review. There were no significant differences between NSM and SSM groups in local recurrence rate . Unfortunately, this complication was sparsely reported, and this result is driven by the study of Lemaine and colleaguesThere is, however, a lower rate of mastectomy skin flap necrosis (MSFN) for NSM , which summarizes complication rates for NSM and SSM, provides useful data for discussion when counselling women for these two techniques as part of the informed consent process. Smokers and diabetic patients, as well as women with large ptotic breasts or those who have undergone radiotherapy, are most likely to have complications such as nipple necrosis or skin flap necrosis with NSM, although the data are not strong or homogeneous enough to show statistically robust correlations. Interestingly, albeit in patients without cancer, residual NAC sensitivity after NSM was low compared with that in a non‐operated control group; thus, patients may also need to be counselled for thisThese findings support the role of NSM in modern breast surgery practice for selected patients. Given the limitations of reporting of complications for NSM, the imminent publication of the UK prospective audit on implant‐based breast reconstruction (the i‐BRA study) may provide more reliable data for NSM and SSM. Further research is needed to help refine the evidence on surgical approaches for NSM to optimize outcomes. For example, knowledge of which incisions minimize nipple and mastectomy skin flap necrosis is needed. Greater understanding of the NAC blood supply and how the various incisions can disrupt this, the interplay of reconstructive techniques with perfusion of skin, and other methods to optimize skin flap viability is required, as well as methods to increase its perfusion. There are no data on learning curves for performing NSM.Gould and colleagues' workversus SSM to date. A rigorous search was performed for evidence to the end of June 2017, using two independent search teams. A protocol for this study was published a priori; it followed Cochrane methodology and is reported in line with PRISMA criteria. This review was not restricted to the English language, and included 3015 breasts from North America, Japan, South Korea and Germany. It scored 11 of 11 on AMSTAR criteriaThis is the most comprehensive systematic review of NSM There were no RCTs suitable for inclusion in the review, and no prospective studies. All included studies were of evidence level 3, and their quality was variable. Using the Cochrane ACROBAT‐NRSI tool, all articles except oneMany of the studies did not provide complete, clear or transparent information. These issues have been highlighted in previous systematic reviews and studies of reporting qualityCase mix and selection bias are important. The NSM group included more prophylactic cases, which are likely to have a lower local recurrence rate than patients with cancer, but significant limitations in the data prevented a sensitivity analysis to look at cancer cases alone. Even within the cancer cohorts, different stages of disease and durations of follow‐up challenge the analysis in a systematic review. The differences highlighted could certainly impact on the results. The Gerber study of 2003et al.The reporting of complications is very variable, with some studies reporting by patient and others by breast. Nonetheless, as these studies reported in the same way for SSM as NSM, they were still included in the analysis of complications. Finally, there is concern about the exclusion of 93 patients in the study by Lemaine Most studies did not report on aesthetic outcome. Those that did used a variety of assessment tools, making comparisons difficult. The lack of reporting of a minimum set of outcomes in a standard way often hampers systematic reviews. It is anticipated that publication bias might be a factor, given all studies should be reporting survival and only fiveThis review provides an up‐to‐date summary of outcomes for NSM relative to the current standard of SSM. NSM is an option for selected women with breast cancer requiring mastectomy: those with no clinical or radiological evidence of nipple involvement. Women should be counselled about the risk of occult involvement, possibly with personalized risk assessmentTable S1 Previous reviews of nipple‐sparing mastectomyTable S2 Quality of previous systematic reviews according to AMSTARTable S3 Electronic search strategyTable S4 Characteristics of the included studiesTable S5 Oncological profiles of patients included in the studiesTable S6 Summary of complication rates in NSM and SSM groups (breasts)Table S7 Clinician and patient‐reported outcomesFig. S1 Number of articles published per year and indexed by Scopus under the search term ‘nipple‐sparing mastectomy’Click here for additional data file.


To compare different methods of indexing health care service prices for the commercially insured population across geographic markets.Health Care Cost Institute commercial claims data from 2012 to 2016.We compare price indices computed using methods with differing levels of computational intensity: weighted‐average versus regression‐based methods. We separately compute indices of the prices paid for set of common inpatient and set of common outpatient services in different markets across the United States using each type of method. We subsequently examined the variation of and correlations between the resulting index values.We computed health care service price indices separately using samples of inpatient and outpatient facility claims from 2012 to 2016 across 112 Core‐Based Statistical Areas. Within each category of services, claims were limited to members under the age of 65 with employer‐sponsored insurance. Both samples were limited to a common set of services that made up nearly 80 percent of the service use in the full sample every year.r > .94) with similar distributions across years for both inpatient and outpatient services.We found that the methods studied produced highly correlated price indices (Our findings suggest that weighted‐average methods, which are much less computationally intensive, will generate results similar to regression‐based methods. Unlike spending variation among the publicly insured, which is primarily attributable to variation in service use, there is evidence that commercial spending variation is also attributable to variation in service prices.We assess how using different methods of benchmarking the transaction prices for health care services across geographic areas affects price measurement. Traditionally, researchers have used less computationally intensive average‐based measures that summarize the prices of a defined set of services.Alternatively, researchers can use more computationally intensive regression‐based approaches to measure medical prices across areas or providers.We compare weighted‐average‐based methods with a regression‐based method of indexing commercial health care prices. We then empirically test whether these different methods produce substantially different price indices to inform the trade‐off of index performance and computational burden.2We leverage data from the Health Care Cost Institute (HCCI) on the allowed amounts paid for 250 million commercial claims spanning 112 Core‐Based Statistical Areas (CBSAs) across 43 states over 2012 to 2016. To construct a service‐level sample, we aggregate data from all claim lines associated with an individual on common dates for the same service. For inpatient admissions, we define a service by the Diagnostic Related Group (DRG) code. For outpatient services, we define the service by the combination of a Current Procedural Terminology (CPT) code and CPT code modifier. We define the total spending for a service as the sum of the allowed amounts for all associated claim lines. The allowed amount represents the actual amounts paid to a provider for a claim—including all insurer and individual out‐of‐pocket payments.We limit our sample to individuals under the age of 65 with employer‐sponsored insurance. We exclude claims with extreme lengths of stay or costs. We use CBSAs as the geographic level to report our analysis. We also limit our analysis to CBSAs where the HCCI database has both sufficient data coverage and density of health care providers. For a complete description of our sample restrictions, see the Appendix In this study, we limit our analysis to inpatient admissions and outpatient facility services. For each category of services, we examine a subset of common services  and service types. Here, g¯ is a vector of sample means for each CBSA indicator:We also predict the average price per service nationally in each year holding constant the average mix of demographics, service types, and patients from each study CBSA. Here, all terms are defined as before and We then calculate a price index for each CBSA‐year observation as the ratio between the predicted price in each CBSA in each year and predicted price nationally in our base year:3.5To compare the variation in the price indices we calculate using each method above, we examine the distributions of each index. We then compute pairwise Pearson correlation coefficients between the indices.44.1Each approach produces wide variation in price index values across CBSAs. However, in our sample, the choice of approach had little effect on the shape of the resulting distribution of those values Figure . For exa4.2In addition to having similar distributions, we also find that the price indices calculated with different methods share a strong positive correlation. In other words, CBSAs with relatively high price levels using a particular approach have similarly high relative prices when using the other approaches. Pairwise scatter plots are presented in Figure 5There are both advantages and disadvantages when computing price indices using each of the three methods discussed in this paper.5.1A and B in a given year is equal to the weighted geometric average of the ratio of average service prices between CBSAs A and B  are included in the basket. Additionally, this approach is also not computationally intensive to implement.The arithmetic average index shares the same limitations caused by selecting sample services and imposing service weights. In particular, it has the same potential limitation due to missing observations for sample services in some CBSA‐year combinations; necessitating either a narrower market basket or imputed data. One additional limitation relative to the geometric average index is that the arithmetic average index does not have the convenient multiplicative properties.5.3The primary advantage of the regression‐based approach is that it more flexibly accounts for missing data. In this way, the regression‐based approach—unlike its weighted‐average counterparts—does not necessitate shrinking the size of the market basket or imputing data when there are no observations for services within the market basket in a given CBSA. Another advantage of the regression‐based approach is it can better account for population heterogeneity both across CBSAs and over time.The main disadvantage of using a regression‐based method is it is computationally intensive. In the context of outpatient services, for example, there are tens of thousands of distinct outpatient services observed in our data. Estimating our regression specification would necessitate the inclusion of that many fixed effects to perform the same analysis on this full sample (rather than for the subset of common services which we studied). Further, when the samples include hundreds of millions of observations, the amount of time and computing power necessary to estimate such regressions can become prohibitive. As a result, researchers might be forced to either use a subset of the observations, limit to a subset of services, or both.5.4The strong correlations between the regression‐based measure and both the weighted‐average indices potentially alleviate concerns about some of the shortcomings of the latter measures. This finding provides evidence adjusting for demographic factors potentially correlated with underlying population health  does not qualitatively change the price indices we compute.Our findings also provide evidence that price indices for medical services are not sensitive to reasonable choices of market baskets—that is, both the set of services studied and the weights of services imposed. We observed strong correlations between indices which flexibly allow for substitution away from high‐priced services (regression‐based) and indices that do not (weighted‐average‐based), both across geographic areas and years. This supports the similar conclusions drawn by previous research.Each approach studied produces largely similar measures of relative commercial health care prices across geographies and over time. These findings echo previous work using a different data source and sample period, as well as surveying a new set of methods. Click here for additional data file. Click here for additional data file.


Eating outside the home is challenging for consumers with food allergy (FA) and intolerance (FI) and lack of allergen information provision in eating out venues can lead to unnecessary restrictions. Following European legislation (2014) designed to improve allergen information provision, little is known about differences in information provision experienced by consumers seeking to avoid particular allergens, or how this impacts on their eating out experiences. This study compared the information provision that consumers with FA/FI to different allergens experience when eating out.n = 66), nuts (peanuts/tree nuts) (n = 94), or milk (n = 74), and responses were subject to quantitative analyses. Interviews were carried out with 49 participants avoiding either gluten (n = 13), nuts (n = 14), milk (n = 13) or a combination of these allergens (n = 9), and analysed using the framework approach.Using mixed methods, participants were recruited from across the UK and took part in self-report surveys or in-depth interviews. Surveys were completed by 232 participants avoiding either gluten  contains supplementary material, which is available to authorized users. Allergen avoidance is a key management strategy for food allergic (FA) and food intolerant (FI) individuals, and eating outside the home represents a particular risk of accidental allergen ingestion  where thEU legislation ) introduced in December 2014 [Given that adverse reactions can occur in response to any of these allergens, differences in the quality of information provided about them is important. Little work has considered the differential impact of seeking to avoid particular allergens or how experiences of seeking to avoid particular allergens vary. Although adherence to an allergen-free diet has been associated with poorer quality of life, and significant social and behavioural restrictions –14, liteAs yet, the eating out experiences of populations seeking to avoid particular allergens has not been considered. In light of the EU FIC legislation, eating out venues are required to provide information about the content of each of the 14 allergens in their foods, and attention has recently turned to the adequacy of this information provision for each allergen. For example, online resources such as ‘Guide to eating out with a food allergy’ , show hoEvaluating the impact of the EU FIC legislation provided the opportunity to compare the information provision that customers with FA/FI experience in relation to different allergens when eating out. In order to investigate this, in a mixed methods study we conducted semi-structured interviews and self-report surveys with customers who avoided particular allergens  following implementation of the legislation. We assessed differences between these groups based on their satisfaction with allergen information provision, and their preferences for written and verbal forms of information delivery.As part of wider programme of longitudinal research into the eating out experiences of adults and parents/carers of children with FA/FI  prior toSurvey participants were recruited from across the UK by a professional market research agency: Acumen Fieldwork-Medical (66%) and using the websites and mailing lists of three UK-based charities: Allergy UK (28%), Anaphylaxis Campaign (3%), Coeliac UK (3%). Between November and December 2016, 392 participants completed the survey. Of these, 188 (48%) had been recruited to complete a prior version of the survey in 2014 and returned to complete the 2016 survey, and 204 (52%) were recruited as new participants to complete the 2016 survey. Of the total 2016 survey population, 232 (59%) participants were included in analyses because they avoided either gluten, nuts or milk when eating out.Participants completed a screening questionnaire to ensure that they met the minimum requirements for inclusion in the study. The inclusion criteria were that participants aged over 18, or their child in the case of parents/caregivers: a) experienced reactions to one or more of the 14 allergens covered by the EU FIC legislation; b) ate out at, or ordered takeaway food from a restaurant, café, coffee shop, fast food outlet, or any other place where they can buy non-prepacked food; c) sought to avoid one or more of the 14 allergens covered by the EU FIC legislation when eating out or ordering takeaway food; d) experienced one or more symptoms typically associated with IgE-mediated food allergy or non-IgE-mediated reactions (classified as food intolerance in this study). Survey results for participants seeking to avoid nuts (tree nuts and peanuts), gluten or milk are reported. Classification criteria are shown in Table n = 20) of participants. Survey subscales included: ‘Reliance on speaking to staff’; ‘Satisfaction with written information’; ‘Staff as an additional information source’; ‘Preference for separate allergen menu’; and two single items-‘Menu invites you to ask staff’ and ‘Sign invites you to ask staff’. All 2014 survey items were retained in the 2016 survey. Full details of subscale items and item reversals are shown in Table We designed an online survey relating to attitudes and behaviours when eating out specifically for the study. Survey design was informed by a literature review, discussions with support groups and interviews conducted in 2014, prior to EU FIC legislation [Following provision of informed consent, participants meeting the inclusion criteria were routed to the survey for completion.p > .05)). Missing values for items within subscales were imputed using expectation-maximization (EM) [p ≤ .05 was used, although post hoc tests approaching significance (p=. 051 – p=. 056) are also reported.Statistical analyses were carried out using IBM SPSS Statistics (v22). Data was screened to ensure no violation of the assumptions of normality, linearity, and homoscedasticity. The extent of missing data (less than 2%) and non-response patterns were assessed to see if missing items would impact on analyses (Little’s MCAR test (ion (EM)  and subsFull details of 2014 interview recruitment procedure, populations and results are reported elsewhere [In-depth semi-structured interviews were carried out in participants’ homes following an interview protocol detailing questions and possible prompts (a copy of this interview protocol can be provided on request from the corresponding author). Each interview was audio-recorded with participants’ permission. Initial questions related to any changes that had occurred in returning participants’ lives; and in relation to their food allergy in particular. The interview then focused on participants’ recent eating out experiences and any changes in these, including their encounters with information about food allergens. They were asked for their reflections and evaluations of these changes, and about the impact of the legislation on allergen information provision in relation to their eating out experiences. Interviews lasted between 27 and 76 min.Interview recordings were transcribed verbatim and explored in detail using framework analysis . Intervin = 121, 31%) and those who avoided an allergen other than gluten, nuts or milk  were excluded from analyses.Characteristics of survey participants are shown in Table Summarised in Table p < .05). Participants avoiding nuts reported a greater reliance on speaking to staff than those avoiding gluten (p = .019), and those avoiding milk (p = .003).There was a significant main effect of ‘allergen’ (gluten/nuts/milk) on participants’ reliance on speaking to staff (p < .05). Post hoc analysis approached significance (p = .053) suggesting that those who avoided nuts were more satisfied that written information could aid confident food choices than those avoiding gluten.There was a significant main effect of ‘allergen’ (gluten/nuts/milk) on participants’ satisfaction with written information (p < .05). Participants avoiding nuts (p = .009) and those avoiding gluten (p = .001) both preferred staff as an additional source of information in comparison to those avoiding milk.There was a significant main effect of ‘allergen’ (gluten/nuts/milk) on participants’ preference for staff as an additional information source (p < .01). Participants avoiding nuts (p = .007) and those avoiding gluten (p = .001) had greater preference for a separate allergen menu as a potential source of information than those avoiding milk.There was a significant main effect of ‘allergen’ (gluten/nuts/milk) on participants’ preference for a separate allergen menu (p < .05). Participants avoiding nuts were more positive about the menu inviting customers to ask about dishes than those avoiding milk (p = .016).There was a significant main effect of ‘allergen’ (gluten/nuts/milk) on participants’ perceptions of a statement on the menu inviting customers to ask staff about dishes (p < .05). Post hoc analysis approached significance (p = .056) suggesting that those avoiding nuts were more positive about the sign inviting customers to ask about dishes than those avoiding milk.There was a significant main effect of ‘allergen’ (gluten/nuts/milk) on participants’ perceptions of a sign inviting customers to ask staff about dishes  were excluded from analyses.Characteristics of interview participants are shown in Table Following implementation of the legislation, three overall themes were described by participants in relation to their observations and experiences of allergen information provision when eating out. Participant responses focused on management of their FA/FI when eating out and related to: ‘disparities in allergen information provision’, ‘understanding the needs of customers avoiding different allergens’, and ‘customer demand for information about specific allergens’.Following implementation EU FIC, the majority of participants had observed general improvements in the provision of allergen information when eating out; though they noted that these improvements were largely focused on the provision of information for customers seeking to avoid nuts or gluten. For many participants, a disparity in allergen-specific information was observed, regardless of the allergen that they themselves sought to avoid Table : quote 1For participants seeking to avoid gluten, the separate ‘gluten-free’ menu was seen as a gold standard which was becoming increasingly available. In the absence of this provision, the use of a symbol or letter displayed beside each dish on the main menu served as a simple and trusted indicator which facilitated food choices Table : quote 2Participants seeking to avoid milk had also observed the improvements in information provision for those avoiding nuts or gluten, but had not seen similar improvements in relation to their own dietary needs. These participants were impressed by the gluten-free provision that was now available, and wished that similar information was available for milk-free diets Table : quote 4Many participants seeking to avoid milk felt that their dietary needs were not well understood, and that this in turn might be leading to a lack of appropriate allergen information provision in eating out environments. Participants noted that many eating out staff failed to understand their need for avoidance of milk as a ‘hidden ingredient’ within many dishes. In the absence of tangible written allergen information, participants used subtle social cues to detect misunderstanding on the part of venue staff Table : quote 1For participants seeking to avoid gluten, the issue of gluten as a ‘hidden ingredient’ coupled with indictors of confusion exhibited by venue staff had been experienced in the past, and were now less common in light of increased staff awareness and improved information provision Table : quote 3One participant, who worked in an eating out venue, provided insights into the relative frequency of customer enquiries about the allergens. They noted that such enquiries were infrequent; relating to the gluten and nuts, but not to the milk content of foods Table : quote 1Using a mixed methods approach, this study indicates that the eating out experiences of consumers with FA/FI differ depending on the food allergen that they are seeking to avoid, and that allergen-based inequities in information provision are impacting on some consumers with FA/FI following the introduction of EU FIC legislation in December 2014. Specifically, not only do those avoiding milk have less positive experiences, but in addition they perceive that the provision made for those avoiding other allergens tends to be better. Participants seeking to avoid milk had also observed the improvements in information provision for those avoiding nuts or gluten, but had not seen similar improvements in relation to their own dietary needs. They noted that many staff in eating out venues failed to understand their need for avoidance of milk as a ‘hidden ingredient’ within many dishes.In general, survey participants reported being moderately satisfied with the availability and adequacy of allergen information provision when eating out, and interview participants suggested that this provision was an improvement on the allergen information made available prior to EU FIC. However, satisfaction levels and perceived improvements in provision differed depending on whether participants sought to avoid gluten, nuts, or milk as ingredients in foods. Amongst survey participants, those seeking to avoid milk were less satisfied with the information provided for their specific dietary needs in comparison to participants avoiding nuts, and to a lesser degree those avoiding gluten. In particular, they were less likely to involve staff in their deliberations about the potential for allergen free meal options- either by asking staff directly about the allergen content of foods or as an additional information resource following inspection of the menu. They were also less likely to take a positive view of written statements inviting customers to ‘ask staff’. Although this is in part unsurprising given that research prior to the implementation of EU FIC indicated that consumers with FA/FI were often reluctant to make enquiries of staff , crucialUnder the themes ‘disparities in allergen information provision’, ‘understanding the needs of customers avoiding different allergens’, and ‘customer demand for information about specific allergens’, in-depth interviews provided insights into the potential reasoning behind participant survey responses. Whilst participants seeking to avoid gluten and nuts reported improvements in written allergen information provision when eating out, those seeking to avoid milk observed no such improvements. It is likely that this post-legislative disparity between groups created feelings of inequity of provision that did not exist prior to the legislation’s implementation, thus fragmenting allergen avoiding populations. This is an important consideration for eating out venues given that consumers with FA/FI tend to equate the adequacy of allergen information provision with wider judgements about the venue’s ‘understanding’, ‘allergen-awareness’ and ‘capacity’ to accommodate specific dietary needs safely . For parThe perceived understanding of the needs of some consumers with FA/FI (nuts and gluten) in comparison to others (milk), led participants seeking to avoid milk to conclude that the implications of their accidental allergen consumption were taken less seriously, and their concerns seen as less legitimate than other allergen-avoiding groups. This distinction has been observed in FA and FI populations, where FI can be viewed as more ‘socially problematic’ than FA, due to the ambiguity of FI symptoms and diagnosis when compared to FA . Some ofEqually, it is important for eating out venues to consider the implications of accidental allergen consumption for customers with severe FA to milk. Whilst FA to peanuts/tree nuts is more common, and the potential for anaphylaxis amongst this population more widely understood, cow’s milk is the most common cause of anaphylaxis amongst UK children  and persThis study is the first to provide insight into the perceived differences in allergen information provision for particular allergens, and most importantly, the difficulties that consumers with FA/FI report when seeking to avoid milk whilst eating outside the home.Alongside their legal responsibilities to provide allergen information for consumers as a result of EU FIC, it is important that eating out providers understand that FA/FI customers are sensitive to inequities in allergen information provision and interpret these as a wider indicator of customer care and food safety in venues. Any such inequities are likely to be magnified for FA/FI customers who seek to avoid ‘staple foods’  which are ubiquitous in the western diet and more difficult to avoid as a result –23. An aHealth professionals , support groups and charities have important contributions to make by educating and encouraging their FA/FI patients- and those avoiding milk in particular - to be confident in requesting and expecting the provision of allergen information when eating out, as they are entitled to do since the introduction of EU FIC. Patients can also be encouraged to use proactive techniques such as informing eating out venues in advance  or carryParticipants self-reported their FA/FI status, and a minority were self-diagnosed alongside those who reported receiving a clinical diagnosis. Entry to the study was through the careful application of symptom-based FA/FI criteria although we recognise it is unlikely that classification of patients as FA or FI would accord with a medical diagnosis. However, our approach of making the distinction between populations based on the allergen that they were seeking to avoid rather than between FA and FI renders this limitation as less problematic. Our approach allowed us to highlight the common difficulties experienced by milk avoiding FA/FI participants, and these difficulties were particularly salient given that no allergen-based differences between FA and FI populations were shown in analyses. Furthermore, in the context of eating out, the distinction between FA and FI becomes less relevant because the legal requirement for venues to provide allergen information applies for all customers and is not contingent on their FA/FI status.We also acknowledge that we took a conservative approach in survey analyses. In order to ensure that responses were attributable to each particular allergen avoided, we only included participants who avoided either gluten or nuts or milk and did not include those who reported avoiding multiple allergens. It is likely that participants who sought to avoid multiple allergens experienced greater difficulties when eating out . Lastly,A mixed methods approach was valuable in exploring the experiences of those seeking to avoid gluten, milk and nuts when eating out. Through the application of surveys and interviews, FA/FI participants reported that there were general improvements in allergen information provision in eating out venues following introduction of EU FIC legislation. However, inequities in the provision of allergen information for particular allergens  led participants seeking to avoid milk to conclude that their dietary needs were less well-understood and seen as less important. These perceptions were reflected in a reluctance to involve eating out venue staff in deliberations about the potential for allergen free meal options, and limited the food choices of those seeking to avoid milk as a result. The provision of visible visual indicators on menus of the presence of milk and increased allergen-awareness training for staff can play a key role in increasing confidence in the eating out venues and improve the eating out experience of customers seeking to avoid milk. Medical professionals also have a key role to play in educating and encouraging their FA/FI patients to pursue their legal right to make allergen enquiries in order to avoid accidental milk allergen consumption when eating out.Additional file 1:Further demographic and background characteristics of survey participants, Description of data: Further demographic and background characteristics of survey participants. (DOCX 14 kb)Additional file 2:n = 149), Nuts (n = 272) and Milk (n = 77) prior to legislation, Description of data: Perceptions of information provision for participants avoiding Gluten (n = 149), Nuts (n = 272) and Milk (n = 77) prior to legislation. (DOCX 14 kb)Perceptions of information provision for participants avoiding Gluten (


One of the most outstanding observations from next‐generation sequencing approaches was that only 1.5% of our genes code for proteins. The biggest part is transcribed but give rise to different families of RNAs without coding potential. The functional relevance of these abundant transcripts remains far from elucidated. Among them are the long non‐coding RNAs (lncRNAs), a relatively large and heterogeneous group of RNAs shown to be highly tissue‐specific, indicating a prominent role in processes controlling cellular identity. In particular, lncRNAs have been linked to both stemness properties and detrimental pathways regulating the aging process, being novel players in the intricate network guiding tissue homeostasis. Here, we summarize the up‐to‐date information on the role of lncRNAs that affect stemness and hence impact upon aging, highlighting the likelihood that lncRNAs may represent an unexploited reservoir of potential therapeutic targets for reprogramming applications and aging‐related diseases. LncRNAs are transcribed majorly by Pol II and Pol I RNA polymerases and are present throughout the genome, either as antisense of coding genes , pseudogenes, or intergenic (long intergenic non‐coding RNAs‐lincRNAs), additionally they could be bidirectional, arise from trans‐splicing or adopt different structural forms which increase their stability Figure a SeveralAging is a biological process characterized by a cascade of biochemical changes which result, ultimately, in an observable functional decay  and subsequent repression of the target gene expression by recruiting Suv39h1 to MyoD‐binding loci. During differentiation, Malat1 is degraded, thus destabilizing the repressive complex and leading to target gene activation. Together, Chen et al. identified a regulatory axis in myogenesis controlled by Malat1, showing an inhibitory role for Malat1 during myogenic differentiation. Linc‐RAM is involved in the differentiation stage of myogenesis by regulating the transcription of MyoG  of miR‐133 and miR‐135 regulating the expression of MAML1 and MEF2C  has been identified in aged muscle   with altered expression between 4mo and 24mo HSCs. Surprisingly, the lncRNAs whose expression was changed with aging were not characterized  are specialized blood‐forming stem cells . Xiao and colleagues described the expression patterns of T‐UCRs in the intestinal epithelium  and E‐cadherin mRNAs  in intestinal epithelial cells (IECs)  comparing to normal‐mucosal samples from controls , which works through activation of the signal transducer and activator of transcription 3  which are epigenetically differentially marked by DNA CpG methylation in the two parental alleles. Interestingly, most imprinted clusters have at least one lncRNA which is mono‐allelically expressed and regulated by CpG DNA methylation. These lncRNAs can be intergenic or antisense to reciprocally imprinted genes. They are believed to regulate imprinted expression of the neighboring genes through the act of transcription itself or by the recruitment of chromatin‐modifying complexes, as has been referred to the cases of Airnc, Kncq1ot1, and Meg3 lncRNAs  and genomic imprinting  is the first important decision that cells undergoing reprogramming need to overcome  need to be taken into consideration in the design of strategies for efficient lncRNA modulation.UBE3A, with the paternal copy of UBE3A being silenced by a lncRNA named UBE3A‐ATS  ameliorated some cognitive deficits associated with the disease (Meng et al., SAMMSON, a lncRNA linked to melanogenesis. Targeting SAMMSON through intravenous delivery of ASO in a human xenograft model significantly reduced tumor growth and cell proliferation (Leucci et al., Modified oligonucleotides are probably the best characterized and known approach to target lncRNAs. Antisense oligonucleotides have been traditionally used as a research tool to explore function of several lncRNAs in vitro and in vivo. More recently, novel oligonucleotides harboring RNA or DNA recognition and cleavage domains have shown up as potential novel strategies with an increased specificity and stability to target lncRNAs independently of their cellular compartmentalization (Bhartiya et al., 4.1Rapid advances in genome sequencing have placed long non‐coding transcripts as a major player in gene regulation. In this review, we placed the current knowledge on the potential roles of lncRNAs in stemness related to aging. On one hand, we discuss functional roles of lncRNAs in stem cell pools during aging and, secondly, their impact on cellular reprogramming of aged cells. We believe that in the near future, functional tests will undoubtedly uncover anti‐aging therapeutic approaches relying on targeting of lncRNAs. We expect many surprises to come, where a complex trait such as aging could be seen at the light of the non‐coding transcriptome.None declared.


Traditionally, wide lateral surgical margins of 3 cm and one fascial plane deep have been recommended for resection of canine cutaneous mast cell tumor (MCT). Several studies have been published assessing surgical margins of less than this traditional recommendation. The objective of this systematic review was to determine if resection MCT with lateral surgical margins < 3 cm results in low rates of incomplete resection and local tumor recurrence. Systematic searches of digital bibliographic databases were performed with two authors (AR & LES) screening abstracts to identify relevant scientific articles. Studies regarding surgical treatment of dogs with cutaneous MCT were reviewed. Data abstraction was performed and the quality of individual studies and the strength of the body of evidence for utilization of surgical margins < 3 cm for removal of MCTs was assessed.From the initial 78 citations identified through the database searches, four articles were retained for data abstraction after both relevance screenings were performed. Two studies were retrospective observational studies, one was a prospective case series and one was a prospective clinical trial. Assessment of the quality level of the body of evidence identified using the GRADE system was low. Excision of MCT at 2 cm and 3 cm was associated with comparably low rates of incomplete excision and recurrence.Despite the low quality of the overall body of evidence, a recommendation can be made that resection of canine cutaneous MCTs (< 4 cm) of Patnaik grade I and II with 2 cm lateral margins and 1 fascial plane deep results in low rates of incomplete excision and local tumor recurrence. Mast cell tumor (MCT) is the most common malignant skin tumor in dogs –4. The bGiven that resection of these wide margins can cause significant patient morbidity, several investigators have assessed decreased lateral margins and the effect on completeness of excision or local tumor recurrence –19. The The results of the literature search and relevance screening is summarized in Fig. Using the GRADE system, the overall quality of evidence for this body of literature was low. This was because the initial quality of the body of evidence was rated as low based on the design of the included studies . Factors that could have increased the overall quality of the body of evidence, such as presence of a large effect size, a consistent dose response relationship, or evidence that plausible confounding, if present, would reduce the demonstrated effect. However, the low risk of bias, the consistency of results, the ability to directly compare outcomes, the lack of imprecision, and the absence of evidence to indicate publication bias has occurred did not lower the overall quality score. Thus, the body of available evidence by which we can assess outcomes related to incomplete excision and local recurrence were classified as low quality overall.The individual manuscripts had between 16 and 55 dogs each, however some dogs had concurrent MCTs removed. In the studies, all experiments were single arm with no control group. All studies assessed cutaneous MCT at any location and only one study allowed inclusion of subcutaneous MCT . Most tuAll studies evaluated dogs with MCT < 6 cm and had surgery to treat MCT with different lateral surgical margins. Fulcher et al. utilized 2 cm lateral margins; Seguin et al. used 2-3 cm lateral margins; Simpson et al. used 3 cm lateral margins, and Pratschke et al. utilized lateral margins proportional to tumor size (5 mm to 4 cm) with the exception of one dog with a 6 cm tumor that received 4 cm lateral margins. Two studies further evaluated different lateral margins with assessment of smaller margins on the resected specimen in addition to the margin taken at surgery. Fulcher et al. assessed 1 cm lateral margins  and Simpson et al. assessed 1 cm and 2 cm lateral margins .Considering all studies, the lateral surgical margins had variable ranges of incomplete histologic excision . The study definition of incomplete excision is outlined in Table Our review of the current literature indicate there is evidence to suggest that the use of lateral surgical margins of < 3 cm for resection of PG I and II MCT less than 4 cm in size are associated with low rates of incomplete excision and local tumor recurrence. Utilizing the GRADE system, the body of evidence was determined to be low quality for surgical margins for MCT. Despite the overall GRADE quality rating of the evidence base, we can still conclude that surgical margins of 2 cm lateral and one fascial plane deep are associated with a low rate of incomplete excision of PG I and II canine MCT (< 4 cm) (0–10.5%) and low rates of recurrence (0%) given the current body of literature –19. ThisThe study populations in the four manuscripts included in this review consisted of dogs with MCT (< 6 cm) of PG I and II. Only one study included 2 PG III tumors and no studies included tumors larger than 6 cm diameter. Increased PG and increased tumor size are both factors that have been previously reported to be associated with more biologically aggressive disease. Large tumors and those with PG III typically have more extensive microscopic disease, which in turn makes them more difficult to completely excise and it is therefore expected they will have higher local recurrence rates , 20, 21.A limitation of this review is that there were differences in the ways the included manuscripts assessed and classified surgical margins as being histologically incomplete. Two studies classified incomplete surgical margins as the presence of mast cells at the surgical margin and two classified margins as incomplete if mast cells were present within 1 mm of the surgical margin. The classification of margins as incomplete can be challenging with MCT due to inherent difficulties with differentiating between neoplastic mast cells and normal mast cells. Also, differences in the number of sections of the surgical margins evaluated may have influenced the number of margins determined to be incomplete. In the manuscripts included in this review, surgical margin assessment was described in detail in the Simpson et al. study with 4 full thickness sections assessed for 1 and 2 cm surgical margins and 8 sections assessed for 3 cm surgical margins. Similarly, the Fulcher et al. study used 4 sections for 1 cm surgical margins and 8 sections were evaluated for 2 cm surgical margins. In the other studies the number of sections assessed was not reported.General limitations of this systematic review should be considered when interpreting the results. Despite an extensive search of multiple databases and identification of a high number of possible studies for inclusion only four published studies that fit inclusion criteria. In addition, the authors did not contact the corresponding author of manuscripts that did not contain details on surgical margins or outcomes to assess if these would also fit inclusion criteria. This may have led to exclusion of some studies where information may have been available. Conclusions made in this systematic review are based on only four papers. With the exclusion of papers not written in English we may have missed possible eligible manuscripts although this number is estimated to be low. It is possible that this review is susceptible to publication bias given only manuscripts published in peer reviewed journals were eligible for inclusion.There is evidence to suggest that most PG I and II MCTs that are smaller than 4 cm in size can be excised completely with 2 cm margins despite the fact that the overall quality of published evidence is classified as low. However, this review should encourage further study in this area, as use of smaller surgical margins can positively influence patient morbidity, owner satisfaction, and reduction in financial burden.A review protocol based on PRISMA was designed prior to initiating this review , Web of Science (1900 to present), Medline (1950 to present), CAB Abstracts (1973 to present), conducted in June 2016. Search terms that described the population, intervention of surgical resection and comparison (< 3 cm vs. ≥ 3 cm) of lateral surgical margins were identified in the Medical Subject Headings (MeSH) database. The complete search string utilized was {[dog OR canine] AND [mast cell tumor* OR mastocytoma OR mastocytosis OR mast-cell sarcoma] AND [surgical margin OR incomplete margin OR dirty margin OR surgical resection OR surgical excision OR surgery OR biopsy] AND }.The citations retrieved from each search were stored in commercially available reference management software.The citations recovered from the literature search process were screened to identify and remove citations that were not relevant to the review. Eligible studies were primary research studies  published in English that reported outcomes of surgical treatment of cutaneous MCT in dogs. In addition, these studies needed to assess surgical margins < 3 cm. Studies that were case reports, review articles, not written in the English language, or those that did not report outcomes  of surgical treatment or that had an incomplete description of surgical margins used were excluded from the review. The relevance screening was a two-stage process.Stage 1 of relevance screening involved two reviewers (AR and LES) independently reviewing each abstract title. Citations proceeded to the second stage of review if both reviewers agreed the citation described primary research assessing the outcome of surgical treatment of cutaneous MCT or did not contain enough information to determine eligibility. When the two reviewers did not initially agree about a citation, a discussion was raised and consensus was determined. If the manuscripts met all inclusion criteria determined for stage 1 of relevance screening and the study was published in English, the manuscript could advance to the next stage of the review. Stage 2 of relevance screening involved evaluation of the full manuscript using the full inclusion criteria and was conducted independently by the same reviewers (AR and LES). Similarly, any disagreements were resolved through discussion and consensus between reviewers.For manuscripts that passed through both stages of review, data were abstracted by one reviewer (LES). The results of the abstraction were assessed by a second reviewer (AR) to determine accuracy and completeness. The data abstracted from individual studies included the author list, years the study was performed and reported, study design, study population, sample size, institution where the study was performed, number of subjects treated with surgery in study, number of dogs with Patnaik histologic grades  (PG) 1, The individual study quality was determined based on multiple criteria including: 1) representativeness of study population; 2) selection of study participants; 3) data collection methods utilized; and 4) statistical and analytic methods used. For assessment of the quality of the entire body of evidence, guidelines developed by The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group were used .The data were described in the form of the resultant narrative review.Additional file 1. PRISMA-P compliant systematic review protocol completed prior to initiation of the review.