Peer recovery support services (PRSS) are increasingly being employed in a range of clinical settings to assist individuals with substance use disorder (SUD) and co-occurring psychological disorders. PRSS are peer-driven mentoring, education, and support ministrations delivered by individuals who, because of their own experience with SUD and SUD recovery, are experientially qualified to support peers currently experiencing SUD and associated problems. This systematic review characterizes the existing experimental, quasi-experimental, single- and multi-group prospective and retrospective, and cross-sectional research on PRSS. Findings to date tentatively speak to the potential of peer supports across a number of SUD treatment settings, as evidenced by positive findings on measures including reduced substance use and SUD relapse rates, improved relationships with treatment providers and social supports, increased treatment retention, and greater treatment satisfaction. These findings, however, should be viewed in light of many null findings to date, as well as significant methodological limitations of the existing literature, including inability to distinguish the effects of peer recovery support from other recovery support activities, heterogeneous populations, inconsistency in the definitions of peer workers and recovery coaches, and lack of any, or appropriate comparison groups. Further, role definitions for PRSS and the complexity of clinical boundaries for peers working in the field represent important implementation challenges presented by this novel class of approaches for SUD management. There remains a need for further rigorous investigation to establish the efficacy, effectiveness, and cost-benefits of PRSS. Ultimately, such research may also help solidify PRSS role definitions, identify optimal training guidelines for peers, and establish for whom and under what conditions PRSS are most effective. Substance use disorder (SUD) is one of the most pervasive and intransigent clinical and public health challenges facing the United States . In many clinical settings, unpaid lay peers are called upon to provide support to patients with SUD across all stages of recovery.SAMHSA has previously defined PRSS as a peer-helping-peer service alliance in which a peer leader in stable recovery provides social support services to a peer who is seeking help in establishing or maintaining their recovery SAMHSA, . This brCommon functions of PRSS include facilitating and supporting patients' engagement with SUD treatment and transition between levels of care , in addition to connecting patients with community based recovery support services and mutual-help organizations in ways not possible for conventional treatment providers who are bound by ethical considerations like not forming dual relationships with patients  that provides broader context for this fast-growing literature. The review also identifies, wherever possible, for whom and under what conditions PRSS may have utility to inform health care and community-based PRSS delivery. We also highlight important gaps in the knowledge base that will inform the direction and scope of treatment and future research in this important, emerging area.A systematic search of the literature (as of 10/13/2018), using the search terms “recovery coaching,” “peer recovery support,” “peer-based recovery support services,” and “individual peer support” in combination with substance use terms, identified 158 records across four publicly available databases . An abstract review removed an additional 17 records: seven book chapters , seven records on non-relevant topics, two review articles, and one article because it reported on a mandated to treatment sample. A full text review removed another 17 records: seven review and ten theoretical articles. The remaining 12 studies were included in the analysis and are summarized in We found seven RCTs, four quasi-experiments, as well as eight single- or multi-group prospective or retrospective studies, and two cross-sectional investigations conducted on this topic. The review included 24 reports from 23 original studies containing a total of 6,544 participants. On average, the reviewed studies included more men than women , although in the majority of studies the racial makeup of samples was diverse, and representative of the populations being studied. Outcomes reported were varied and included self-reported and bioassayed substance abstinence vs. non-abstinence, Addiction Severity Index scores , with OR's 1.51–1.57. This favorable abstinence outcome, however, was not supported by bioassay results; no significant between group differences were observed for bioassayed drug use. Similarly, Addiction Severity Index drug subscale and medical severity scores were not significantly different, and no group differences were noted in detoxification or treatment admissions among those who were abstinent. It is possible that a brief, single-session peer interaction is not sufficient to elicit statistically significant levels of behavior change in individuals with SUD. This does not necessarily preclude the possibility that more intensive or sustained peer contact would achieve this end.Bernstein et al.  conducteN = 228). Participants were adult outpatients with severe mental illness who had criminal charges within the 2 years prior to study enrolment. Though having an SUD was not required for study participation, the majority of study volunteers had either a primary or secondary SUD diagnosis. Over the 4-month study period participants attended an average of 66% of Citizenship Training classes, and met once weekly with their peer-mentor. A significant group × time interaction showed participants randomized to the peer support group showed reduced alcohol use over 6- and 12-month follow-up as measured by the Addiction Severity Index alcohol use subscale , while controls demonstrated increased drinking over the same periods. A similar group × time interaction was not reported for drug use measured by the Addiction Severity Index drug use subscale, although from baseline to 6-month follow-up the peer support group showed reduction in drug use (d = −0.62), while the Citizenship Training group showed an increase (d = 0.27). From baseline to 12-month follow-up, however, both groups showed reductions in drug use, though the effect size of this reduction was notably larger for the group receiving peer support . It is not clear, however, whether these effects were driven by the Citizenship training itself, peer support, or a combination of the two. Also, given only 31% of the sample had alcohol use disorder, it is not clear how clinically meaningful this reduction is. Both control and experimental groups demonstrated significantly less non-alcohol drug use and had fewer criminal justice charges over the 12-month study period signaling that on these measures, Citizenship Training + peer support did not perform better than standard clinical treatment alone.In a demographically similar sample, and using a more protracted treatment protocol, Rowe et al.  comparedN = 345). Participants were randomly assigned to a standard referral in which they were given a schedule for local 12-step meetings and were encouraged to attend, or intensive referral to 12-Step that included linking patients to 12-Step volunteers and using journals to check meeting attendance. For those receiving intensive referral, counselors arranged a meeting between the patient and a participating member of a local Alcoholics Anonymous or Narcotics Anonymous group by calling the peer volunteer in-session to arrange for them to meet patients before a 12-Step meeting so that they might attend the meeting together. Intensive referral was associated with greater likelihood of being involved with 12-Step groups and better alcohol and other drug use outcomes over a six-month follow-up period. Subsequently, Timko and Debenedetti (d = 0.23), as well as high rates of abstinence (OR = 1.61).Three RCTs have also been conducted in which peer volunteers from 12-Step groups were brought into the clinical milieu to help connect patients receiving outpatient treatment for SUD to 12-Step programs in the community. Timko et al.  developeenedetti  followedd = 0.89). Similarly, these participants were also more likely to have attended other 12-Step program meetings, and had greater frequency of attendance at these meetings (d = 0.25). They also had less past 30-day drug use (d = 0.30) and fewer psychiatric symptoms (d = 0.28). No differences were observed for alcohol use and notably only 23% of patients in the intensive-referral group actually attended a Double Trouble in Recovery meeting during the 6-month follow-up period compared to 13% in the standard referral group, suggesting about one-fifth of participants receiving intensive referral were driving the observed between group differences.Later, Timko et al.  employedN = 151). Patients were randomized to either, (1) introduction and referral to 12-Step by a peer who shared their own recovery experience with the participant, (2) introduction and referral to 12-Step by a doctor, or (3) no introduction or referral (control group). Peers and doctors were instructed to initiate and maintain an open dialogue with participants about their beliefs, concerns, and experiences with 12-Step meetings, and to address any concerns or misconceptions that clients may have held about 12-Step meetings. Together, peer and doctor referral to 12-Step led to increased attendance at 12-Step meetings during inpatient treatment (88 vs. 73%), though peer and doctor groups had similar rates of 12-Step meeting attendance on the inpatient unit . Rates of post-discharge meeting attendance, however, were significantly higher in the peer referral group  compared to the doctor referral (48%) or no referral groups (33%). Further, participants who attended 12-Step meetings while inpatient were three times as likely to have attended meetings post-discharge than those who did not attend 12-Step meetings while inpatient (59 vs. 20%), and post-discharge meeting attenders reported significantly higher abstinence rates at 3-month follow-up (60.8 vs. 39.2%). Abstinence rates at 3-month follow-up, however, did not differ significantly across intervention groups. Taken together, findings suggest introduction and referral to 12-Step programs for individuals in inpatient detoxification increases 12-Step meeting attendance both during inpatient treatment and after discharge, and that meeting attendance is associated with higher abstinence rates; it is not necessarily important, however, that these referrals/introductions be peer-delivered.Manning et al.  sought td's = 0.33 and 0.63 respectively vs. TAU only). Taken together, findings suggest that at least in terms of treatment adherence, compared with TAU alone, interventions including peer support or peer delivered ministrations are superior. Substance use outcomes were not reported.In contrast to the aforementioned studies, which utilized either single session, peer-delivered intervention , and alcohol use disorder symptom endorsement (d's = −1.23 and −1.47 respectively vs. TAU only). Those in the Engage Program also viewed getting help for their alcohol use problems as being more important compared to those receiving TAU only (d = 0.69), though differences between those receiving peer support and those receiving TAU with skills training were not significantly different. Notably, Participants in the Engage group had significantly greater increases in self-criticism from baseline to 3 months compared to those receiving TAU (d = 0.43), which the authors posit may be a function of peer staff holding up higher expectations for their clients than clinical staff. Additionally, 6 months into the study, participants in the Engage Program had greater duration of outpatient service use compared to those in the TAU group (d = 0.31). At 9-month follow-up, skills training, and skills training with peer support was associated with fewer positive psychotic symptoms and greater functioning in comparison to TAU only, suggesting no specific effect of peers on these measures at this measurement time point. Participants in the peer support and skills training only groups also had significantly fewer psychiatric hospital readmissions from baseline at 6 and 12 months compared to the TAU group, though the peer support and skills training only groups were not significantly different from one another on this measure.Most recently, O'Connell et al.  recruiteTaken together, the RCTs reviewed here had a number of strengths, including strong research designs, provision of manualized treatment for the clinical components of studies  and their spouses (n = 4) in a sparsely populated, rural area. Participants were randomly assigned to either a standard referral procedure which involved receiving information about Alcoholics Anonymous or Al-Anon, and providing information concerning time, date, and location of weekly meetings with encouragement to attend (control group), or to systematic encouragement and connection to 12-Step groups that involved a phone call being made in a counseling session to an Alcoholics Anonymous or Al-Anon member, who had volunteered to provide peer support. The 12-Step group member briefly talked to participants about 12-Step meetings, offered to give a ride to a meeting or meet them before a meeting, and followed up with a call the night of the meeting to remind them about it and to encourage them to attend . One hundred percent of the experimental group attended an Alcoholics Anonymous or Al-Anon meeting within 1 week of referral and continued to attend, whereas none of the control group attended a meeting. The mean attendance rate over four-week follow-up was 2.3 meetings for the experimental group and zero for controls, and (d = 2.74). It is possible that peer linkage helped individuals surmount barriers to attending initial 12-Step meetings due to factors like distance needed to travel to meetings such rural areas.Quasi-experimental studies addressing PRSS generally align with findings from the aforementioned RCTs. In an early study investigating the potential of PRSS, Sisson and Mallams  sought tn = 19). During visits, which would typically last between 30 and 60 min, peers would explain how involvement in mutual-help programs was an essential part of their recovery from SUD. The control group (n = 80) consisted of usual care in which mutual-help meetings were available every evening, but attendance was not required. The authors found that the brief, single-session peer-delivered counseling intervention resulted in greater likelihood of completion of medical detoxification and not leaving “against medical advice” (88% completion vs. 74%). Although peer visits did not result in statistically significant differences in mutual-help meeting attendance following detoxification (p = 0.05), observed differences were clinically meaningful (90% attendance for those receiving peer visits vs. 64% for those not). Similarly, likelihood of abstinence from all substances seven days after discharge was 84% for those receiving peer visits vs. 59% for those not (p = 0.06), and initiation of professional aftercare treatment at 1-week follow-up post detoxification discharge was 100% for those receiving peer visits vs. 82% for those not (p = 0.06). While many detoxification sites invite 12-Step groups to bring meetings into units, this work suggests the possibility of added benefit to allowing 12-Step group members to meet individually with patients to share their experience of recovery, and encourage and support meeting attendance.In a similar study with a sample of patients hospitalized for alcohol and other drug detoxification, Blondell et al.  utilizedN = 19), the authors found that 10 individuals who participated in a peer-driven program based on recovery community model published by SAMHSA and did not relapse, reported increased perceived emotional/informational (R2 = 0.39), tangible (R2 = 0.24) and affectionate support (R2 = 0.24) from pre- to post-intervention. Additionally, participants receiving the peer-support recovery program had lower rates of return to homelessness (85 vs. 33%) over a 6-month period, compared to a sample of residents living in the permanent supportive housing setting 6-months prior to instigation of the peer-support program. Further, prior to institution of the peer program, residents had a 24% chance of relapse to substance use, while the risk for those residents participating in the program was 7%, though it is not clear if this difference was statistically significant and no demographic or clinical data were provided for this comparison group.Work by Boisvert et al.  indicateN = 333). Over 12 months, MISSION provides temporary housing, and delivers integrated mental health and SUD treatment delivered via Dual Recovery Therapy , and a greater decline in the number of psychiatric hospitalization nights compared to those receiving TAU only (d = −0.26). Both groups, however, showed improvement on measures of substance use and associated problems at 12 months, though those receiving MISSION were less likely to drink to intoxication (OR = 0.29) and experience serious tension or anxiety (OR = 0.53). Given the broad treatment platform in this study, it is impossible to separate out peer effects. The findings nevertheless speak to the promise of integrating peer supports with clinician-delivered treatments.Working in the Veteran's Administration system, Smelson et al.  assessedN = 1,362), James et al. (d = 0.16), as well as higher rates of any treatment service initiation compared to no peer contact (96.9 vs. 89.9%). However, when the authors used a more restrictive definition of service initiation—limited to initiation of individual, group, or family counseling, 84.88 and 82.53% of individuals referred to the enhanced and standard programs, respectively, initiated these services. Those receiving PRSS were less likely to complete treatment (26.64 vs. 38.12%), however, among those completing treatment, the average length of treatment was significantly greater for the PRSS + TAU group than controls (d = 0.35). Additionally, participants who had received PRSS who discontinued treatment remained in treatment longer than controls who discontinued treatment (d = 0.36). Groups, however, were not significantly different in terms of total numbers making it to initial assessment appointments, initiating counseling, or discontinuing participation in treatment. Notably, relative treatment dropout rates were very high for both the PRSS (56.9%) and control groups (52.9%), though the difference was not statistically significant (p > 0.05). Also, effect sizes were generally small suggesting the large sample size may have been driving observed statistically significant effects.Most recently, in a large sample of parents or caregivers referred by child protective services to a specialized SUD outpatient treatment program , results intimate the authors' brief peer-counseling intervention may increase participants' recognition that their alcohol and other drug use is problematic, and increase the likelihood of steps being taken to address their alcohol and other drug use. The authors highlight the difficulty in identifying and retaining peer counselors for a majority of the rural U.S. areas where this pilot study was implemented, speaking to some of the real-world challenges associated with implementation of PRSS, especially in already underserved geographic areas. This observation speaks to the potential utility of peer coaching via telemedicine . Survival analysis results over a 3-year period indicate that peer-support program participants had longer periods living in the community without rehospitalization, and a lower overall number of rehospitalizations, compared to a sample of comparable controls not engaged in peer-mentorship.Using government public health, and Medicaid records, Min et al.  retrospeN = 509). Peers work closely with program staff and receive extensive training and supervision. Study participants included women and men over the age of 18 who had SUD and histories of incarceration. From baseline to 12-month assessment the authors observed increases in self-efficacy, perceived social support, and quality of life, as well as decreases in perceived stress, though guilt- and shame-based emotions increased over the same period of time.Similarly, Andreas et al.  shared pN = 152). The authors found retrospectively that 6 months following RAP participation, 86% of their clients reported no past 30-day alcohol or other drugs use, and another 4% indicated reduced use. Further, 95% reported strong willingness to recommend the program to others, 89% found services helpful, and 92% found provided materials helpful.Work by Armitage et al.  suggestsN = 242). Women were more likely to utilize the peer-led outreach service if they were at higher risk due to factors such as seeing >10 clients per week, working in isolated settings, injecting cocaine, or injecting/smoking methamphetamine in past 6 months. Utilizers of the peer-led service, however, were also more likely to access the intervention's drop-in center, and notably, after statistically controlling for inter-individual differences, past 6-month use of the peer-led outreach program was associated with a 4-fold increase in the likelihood of participants utilizing detoxification and/or inpatient SUD treatment.Using a multi-group prospective design, Deering et al.  sought tN = 224). The authors found that participants completing 6-month follow-up (29%) had significant reductions in past 30-day alcohol (d = −0.78) and other drug use (d = −0.64). Participants were also more likely to have attained housing and employment. Symptoms of anxiety and depression, however, were not significantly changed. The low follow-up rate (29%) for this study, however, suggests the possibly of selection bias; i.e., individuals lost to follow-up were doing worse and are not represented in the results, making intervention look better than it actually was. As such, these results should be interpreted with caution.In a retrospective single group study, Kelley et al.  exploredper se, they served in this instance, as a critical link to treatment and were able to accomplish in the field what may be difficult for a non-peer provider.Most recently, Scott et al.  piloted N = 151). Using ED electronic medical record review, they contrasted this intervention to provision of naloxone with written and video instructions on use + usual care, and usual care only. Peers were employed by the partner community-based peer recovery organization. Participants were assigned to one of the three treatment groups based on provider and patient discretion. Peers met with participants in the ED and assessed their readiness to seek treatment, identified overdose risk factors, and provided individualized support and addiction treatment navigation, including linkage to medication for opioid use disorder at the time of, and at least 90 days after the ED visit. The authors did not find significant differences between groups at 12-month follow-up via electronic medical record review; groups were similar in terms of proportion of participants initiating medication for opioid use disorder, number of times returning to the same emergency department for overdose, number of deaths, and median time to death.Also interested in the benefits peers can confer for individuals with opioid use disorder, Samuels et al.  exploredWhile the majority of these single- or multi-group prospective or retrospective studies speak to the promise of PRSS, they should be considered in the light of significant methodological limitations associated with these research designs. Single-group prospective and retrospective designs lack control groups; it is therefore not possible to know if some of the positive findings presented here reflected natural improvements in psychosocial functioning commonly observed in SUD interventions. Relatedly, in multi-group prospective and retrospective studies where comparison groups are used, groups are not selected by random assignment. As such there is risk for selection bias, although the majority of studies reported here checked for demographic between-group differences in order to mitigate this risk. Risk for selection bias is further increased because these studies did not use intent-to-treat analysis; it is thus possible that the benefits conferred by these programs are inflated. Further, all peer-based programs reported here included a wide range of activities and types of support. It is therefore not possible to parse out the unique effects of peers in the context of these interventions.N = 56). They found that although there were no between-group differences in overall treatment satisfaction, women receiving ongoing SUD counseling from a peer-counselor were more likely to describe their counselors as empathic, to identify them as the most helpful aspect of the program, to utilize other clinic resources, and to more strongly recommend the treatment program, compared to clients receiving counseling from traditional providers. This work speaks to the ability of peers to establish rapport in patients. It does not however speak to quality of care or treatment outcomes. It is unclear whether professional-delivered treatment may benefit them more in terms of treatment outcomes, even though patients may feel greater affinity for peer counselors.The cross-sectional literature tentatively speaks to the potential of PRSS-based interventions in a range of treatment settings. Sanders et al.  sought tOne study has also assessed the motivation of individuals in recovery from SUD to seek PRSS. Wanting to know more about university students participating in peer-based college recovery support services, Laudet et al.  surveyedAlthough a strong theoretical case has been made for the potential utility of PRSS in a range of SUD clinical and care settings (e.g., White and Evans, In theory, peer supports such as recovery coaches may have particular utility in hospital and clinical outpatient settings since many individuals with SUD who are not yet engaged in treatment present to these sites with SUD-related medical problems. Peers are uniquely positioned to engage such individuals and help connect them with SUD treatment, either in hospital systems, or the community. Bernstein et al.  showed tPRSS may be especially beneficial in substance detoxification units, since successfully connecting individuals to care following detoxification is a persistent and vexing problem for providers. PRSS might also impact the culture of detoxification units by offering a multiple pathways to recovery approach. Blondell et al.  found thThe evidence reviewed here also suggests peer supports may have the ability to improve outcomes for individuals engaged in inpatient or outpatient psychiatric treatment for SUD and co-occurring mental disorders. In such contexts peer supports have been shown to reduce substance use (Rowe et al., Presently in the Unites States, state-to-state regulations vary greatly in terms of training and credentialing requirements for peer workers (London et al., Community-based SUD programs also utilize PRSS. Research summarized in this review suggests peer recovery supports integrated into community outreach programs may increase individuals' self-awareness of problematic substance use (Boyd et al., Relatedly, peers may also have potential to bolster harm reduction programs. Ashford et al. , for insThe findings reviewed in the present paper should be tempered by the fact the discussed RCTs did not use an intent-to-treat design, potentially introducing sample bias into the results. Additionally, to date, all RCTs studying PRSS have recruited participants with fairly severe SUD and co-occurring mental illness, and major impairment in psychosocial functioning. It is therefore not clear how these results might generalize to samples of individuals with less severe SUD presentations, and those without psychiatric comorbidity. The vast majority of SUD treatment in the US is level-I outpatient treatment, yet to our knowledge there are no studies that have examined the utility of providing peer supports/recovery coaches in these settings. It should also be highlighted that, by nature, much of the non-RCT research presented here is based on convenience sampling, and survey analysis. More RCTs are needed on this topic to validate, and expand upon reported findings.This comprehensive, systematic review of the existing PRSS literature speaks to both the potential of peer supports across a number of SUD treatment settings, as well as the great amount of work yet needed to establish the efficacy and effectiveness of such ministrations. Importantly, many ethical and practical challenges remain for this novel class of interventions for SUD. For instance, individuals providing peer support face boundary issues as their work typically lies at the intersection of purely-peer, and purely-clinical support roles (Jack et al., JK, BH, and BB conceived the project. LH, CV, and AA conducted literature search. DE and JK wrote manuscript. LH, CV, AA, BB, BH, and CW provided revisions and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Familial Mediterranean Fever (FMF), an autoinflammatory disease, is characterized by self-limited inflammatory attacks of fever and polyserositis along with high acute phase response. Although colchicine remains the mainstay in treatment, intolerance and resistance in a certain portion of patients have been posing a problem for physicians.Like many autoimmune and autoinflammatory diseases, many colchicine-resistant or intolerant FMF cases have been successfully treated with biologics. In addition, many studies have tested the efficacy of biologics in treating FMF manifestations.Since carriers of FMF show significantly elevated levels of serum TNF alpha, IL-1, and IL-6, FMF patients who failed colchicine were successfully treated with anti IL-1, anti IL-6, or TNF inhibitors drugs. It is best to use colchicine in combination with biologics. Familial Mediterranean fever (FMF) OMIM #249100) is the most common autoinflammatory disease (AID) worldwide 00 is the. Althoug2 in size with sharp boundaries. In children, those lesions may be the presenting feature of FMF [FMF is characterized by self-limiting episodes of fever associated with serositis, arthritis, and dermal manifestations which last 12–72 h. The interval between the episodes is variable . FMF hase of FMF . Proteine of FMF . Renal ae of FMF , 16.In 1997, FMF was found to be associated with the MEFV gene on chromosome 16 , 6, 17. The temperature is normal or lower than 38 °CThe attacks are longer or shorter than specified (but not shorter than 6 h or longer than a week)No signs of peritonitis during the abdominal attacksThe abdominal attacks are localizedThe arthritis involves joints other than those specifiedThe diagnosis of FMF is based on the Tel-Hashomer clinical criteria. Livneh et al.  noted thThe attacks that do not fulfill the definition for a typical or incomplete attack are not considered as FMF attack . MediterIn January 2016, The European League Against Rheumatism (EULAR) recommendation set for the management of FMF has been published supported by the best available evidence . The goaColchicine has been the main treatment of FMF since 1972 . ColchicProper management of FMF includes trying colchicine up to 2 mg a day until the flare settles. The dose is reduced to 0.5 or 1 mg daily in the time when CRP or preferably serum AA protein is checked weekly for at least 8 weeks to see whether the acute-phase response is high. In that case, treatment is escalated with a higher dose of colchicine. If there is no control of FMF manifestations, other treatments are added to a low dose of colchicine . PatientBecause elevated levels of IL-1 are related to inflammatory activity, the use of drugs targeting IL-1 have been proposed. Three different types of IL-1 receptor antagonists are available. Anakinra is a human recombinant un-glycosylated analog of the IL-1 receptor antagonist. Rilonacept is a fusion protein that contains the extracellular portions of type I IL-1receptor and IL-1 receptor accessory protein. Canakinumab is a fully humanized monoclonal antibody of the class IgG1 that acts specifically against IL-1 beta .Before 2003, Anakinra was successfully tested for the treatment of multiple autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus (SLE). In 2003, 5 patients with Muckle-Wells Syndrome which is a milder form of FMF responded successfully to a trial of Anakinra . The firCanakinumab is the only FDA-approved cytokine blocker for the treatment of colchicine-resistant FMF in the United States . The firThere has been some relatively large randomized studies that tested the efficacy of Canakinumab and/or Anakinra in treating FMF attacks. Meizner et al. treated 7 patients with recurrent FMF attacks with Anakinra or Cankinumab along with colchicine on board. The regimen was beneficial to all patients  .A study by Cetin et al. included 20 patients in whom Colchicine was considered ineffective. Twelve patients received anakinra, and 8 patients were treated with canakinumab. Only 1 patient did not respond to the Anakinra. A significant decrease in proteinuria in the amyloidosis complicated FMF patients was observed . BasaranIn February 2008, rilonacept received the approval from the FDA for the treatment of two Cryopyrin-associated periodic syndrome (CAPS) disorders, namely, familial cold-induced autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), for children and adults 12 years and older . As a prIn 1991, Schattner et al.  studied In clinical settings, tocilizumab (TCZ), an IL-6 receptor blocker, has been widely used for the treatment of rheumatoid arthritis (RA). The first cases reported on the success of tocilizumab in the treatment of FMF came from Japan –112. YilJanuse kinase inhibitors have been well studied for the treatment of RA . TofacitFamilial Mediterranean Fever (FMF) is the most common autoinflammatory disease. A mutation of the MEFV gene on chromosome 16, which codes for protein pyrin, is associated with the disease pathogenesis. Colchicine, which has been prescribed to treat FMF since 1972, remains the mainstay for treatment although its use has been complicated by resistance and intolerance in a minority of patients. Since FMF patients have high levels of certain cytokines, practitioners have found in biologics a solution for colchicine resistant and intolerant cases given the success that biologics have shown in other autoimmune and auto-inflammatory diseases. Anti-interleukin 1, anti-interleukin 6, anti-TNF, and Janus Kinase inhibitors drugs, can be beneficial add-on to colchicine in treating FMF manifestations.


Background: The panel-reactive antibodies that use the complement-dependent cytotoxicity test (PRA-CDC) are still a standard method for monitoring the degree of immunization in kidney transplant candidates on active waiting lists in some countries, including Poland. The aim of this study was to analyze the relationship between the maximum and the last pre-transplant PRA titer on the percentage of positive cross-matches and rate of early acute rejection episodes. Material and methods: The retrospective analysis included 528 patients from two transplant centers. All patients were divided into three groups, depending on their peak and last pre-transplant PRA titers. There were 437 (82.8%) patients with peak PRA <20%  and 91 (17.2%) patients with peak PRA >20%. Among the latter group, 38 had maintained PRA level >20% at the time of transplantation , whereas 53 had pre-transplant PRA ≤20% . Results: The percentages of positive crossmatches were 76.9% in ST and 53.7% in prev-ST groups versus 18.4 in non-ST group (both p < 0.001). The acute rejection rates were 18.9, 17.6 and 6.8%, respectively (p < 0.001 for ST or prev-ST versus non-ST). The pre-transplant PRA titer drop did not decrease the risk of early acute rejection [OR = 1.09 (95% CI: 0.31–3.85)] in a multiple logistic regression analysis. The occurrences of primary graft non-function and delayed graft function were similar in all study groups. Conclusions: Previously immunized kidney transplant candidates even with substantial decrease in pre-transplant PRA-CDC levels are still at high immunological risk when compared with non-immunized patients, and they should receive lymphocyte-depleting induction therapy. The panel-reactive antibody (PRA) test is a routine screening measure to assess the degree of a potential kidney recipient’s sensitization, as a result of prior exposure to external HLA antigens during previous blood transfusions, pregnancies, or organ transplantations . PRA titDespite enormous progress in the field of anti-HLA antibody detection and the assessment of the potential kidney transplant candidate’s degree of sensitization, the number of countries have not introduced the universal single bed antigen detection among waiting list patients, mostly due to the shortage of financial resources ,6. In soThe aim of this study was to analyze the effect of the peak and the last pre-transplant PRA titers on the percentage of positive crossmatches, delayed graft functions (DGF), primary graft non-function (PGN), and early acute rejection (AR) episodes. In order to increase the statistical strength, we have performed our analysis based on patients transplanted in two Polish transplant centers.This retrospective analysis included 528 out of 1078 consecutive kidney transplant recipients (KTRs): 327 in the Silesian (transplanted in years 2012–2017) and 201 in the Pomeranian (transplanted in years 2012–2015) centers in Poland who met the inclusion criterion; i.e., more than 5 completed (positive or negative) crossmatches performed via the countrywide kidney transplant matching system before successful transplantation, including the last one at the day of transplant. The final analysis was carried out in March 2018. In Poland, during each donor-recipient matching procedure the recipients are finally chosen out of the list of patients with a negative crossmatch, based on the higher number of transplant points. We have excluded living donor transplants, simultaneous pancreas-kidney recipients and those KTRs who have been classified and transplanted in an urgent mode due to a lack of dialysis vascular access. No patient was transplanted across the positive crossmatch. This investigation was carried out following the rules of the Declaration of Helsinki. The Bioethics Committee of the Medical University of Silesia granted the permission for this study, informed consent was not deemed necessary as the study does not fulfill the criteria of a medical experiment (KNW/0022/KB/284/15). All data were analyzed anonymously based on the prospectively maintained databases of both transplant centers.All patients were divided into three groups, depending on their maximum and last pre-transplant PRA titers. The majority of the patients had maximal PRA titer <20% and were allocated to the non-sensitized group (non-ST). Patients with both maximal and the last pre-transplant PRA >20% formed the currently sensitized group (ST). Patients with maximum PRA titer >20%, but a pre-transplant PRA <20%, were characterized as a previously sensitized group (prev-ST).The immunosuppressive protocol data and early kidney graft outcomes were reported by both transplant centers. All patients received a triple immunosuppressive regimen, based mostly on tacrolimus, mycophenolate mofetil or sodium, and steroids. In a whole study group, 45.1% of patients were treated with induction therapy, using basiliximab (27.3%) or antithymocyte globulin (18.1%).Early kidney graft function was assessed including PGN, DGF, and AR episodes. DGF was defined as a need of dialysis therapy within the first post-transplant week. Early AR during the first post-transplant hospital stay [mean 21 (95% CI: 20–22) days] was defined based on a clinical diagnosis, confirmed by kidney biopsy. The type of AR  was also analyzed.2 tests for trend. Correlation coefficients for PRA titers were calculated according to Spearman due to their nonparametric distribution. In the combined subgroup of prev-ST and ST patients we performed logistic regression analysis for the occurrence of acute rejection episodes as a dependent variable, with potential explanatory variables selected on the basis of univariate analysis . The threshold for statistical significance was set at 0.05.For the statistical analyses, the 12.5 version of Statistica software  was used. Distribution of the examined variables was checked by the Shapiro–Wilk test. Data was presented as mean values and 95% confidence interval. Categorical variables were compared using ANOVA and χThere were 437 (82.8%) patients with peak PRA <20% (non-ST) and 91 (17.2%) patients with peak PRA >20%. Among the latter group, 38 patients had maintained PRA level >20% at the time of transplantation , whereas 53 patients had pre-transplant PRA ≤20% . The clinical characteristics of three study subgroups are given in There was a significant difference in the time of dialysis therapy before transplantation, however, the dialysis vintage of patients from ST and prev-ST subgroups was similar . Also, tp < 0.001). Of importance, in prev-ST patients the percentage of positive cross-matches was also significantly greater (53.7%) than in the non-ST group. There was a stronger correlation between the percentage of positive cross-matches and peak PRA  than between the percentage of positive cross-matches and last pre-transplant PRA .The percentage of positive cross-matches among all such procedures performed during the time on an active waiting list was 76.9% in ST group versus 18.4% in non-ST group , whereas humoral rejection episodes were the most common type in the ST group . The percentages of vascular rejection were similar in all groups. In addition, the percentage of positive cross-matches was significantly higher in patients with AR than those without AR .The overall incidence of DGF, PGN, and AR in the whole study group was 28.0, 1.7, and 8.5%, respectively. There were no significant differences in PGN and DGF occurrence in all study groups. Contrary, the rates of AR episodes in the early post-transplant period were significantly higher in both prev-ST and ST groups in comparison to the non-ST group . MoreoveThe multiple logistic regression analysis performed in the combined subgroup of prev-ST and ST patients revealed that the pre-transplant PRA titer drop does not decrease the risk of an early acute rejection episode. In this analysis, only HLA class II mismatch was significantly associated with the increased risk of AR .In this study we have demonstrated that previously sensitized kidney transplant candidates with last pre-transplant PRA-CDC level <20% still present a substantial level of sensitization. It resulted in a large percentage of positive crossmatches during waitlisting, and in the frequent occurrence of early AR as compared to never-sensitized patients. In previously sensitized patients, in fact, the frequency of AR was quite similar to patients with persistently positive PRA titers, whereas the percentage of positive crossmatches was much closer to the latter group than to the non-sensitized group. Importantly, as high historical but low current PRA titers were usually recognized as low-immunological risk at the time of transplantation, those patients have often received less powerful induction regimen, with only 47.2% treated with a polyclonal antibody in the study group.When analyzing the kidney graft survival, it was clearly demonstrated that it is markedly affected by the increased pre-transplant PRA titer ,8,9. MorThe most important conclusion of our work is that potential kidney transplant recipients with high historical, but a current PRA titer of <20%, are more prone to receive non-optimal induction therapy with basiliximab or even no induction, if the results of current solid-phase cross-match assays are not available. Such a non-optimal choice of induction might be further caused by the most often used PRA titer thresholds for highly-sensitized patients (>50 or >80%). As a consequence, a long-term graft survival may be worse in these patients . Nevertheless, even in patients with known anti-HLA pre-transplant status, PRA titer remains essential information, determining the clinical decisions. On the other hand, based on single antigen bead testing, a so called virtual panel reactivity (vPRA) value is calculated that reflects the percentage of organ donors that are not eligible for the patient . VirtualOur study was limited by the lack of routine protocol biopsies in the analyzed cohort of patients. Secondly, there were some differences in immunosuppressive regimens between these two transplant centers. Lastly, PRA–CDC tests were performed according to the same protocol in two laboratories (one per center), however no comparison between these laboratories was done.In summary, kidney transplant candidates with a substantial decrease in pre-transplant PRA-CDC level during waitlisting are still at high immunological risk as compared with non-sensitized patients, and should receive lymphocyte-depleting induction therapy. The peak  PRA titer is a valuable marker of sensitization in the lack of solid-phase cross-match assays before transplantation.


To make a systematic review of risk factors, outcomes and prevalence of extended-spectrum β-lactamase-associated infection in children and young adults in South-East Asia and the Western Pacific.Up to June 2018 we searched online databases for published studies of infection with extended-spectrum β-lactamase-producing Enterobacteriaceae in individuals aged 0–21 years. We included case–control, cohort, cross-sectional and observational studies reporting patients positive and negative for these organisms. For the meta-analysis we used random-effects modelling of risk factors and outcomes for infection, and meta-regression for analysis of subgroups. We mapped the prevalence of these infections in 20 countries and areas using available surveillance data.Of 6665 articles scanned, we included 40 studies from 11 countries and areas in the meta-analysis. The pooled studies included 2411 samples testing positive and 2874 negative. A higher risk of infection with extended-spectrum β-lactamase-producing bacteria was associated with previous hospital care, notably intensive care unit stays ; antibiotic exposure ; and certain co-existing conditions. Empirical antibiotic therapy was protective against infection . Infected patients had longer hospital stays  and higher risk of death . The population prevalence of infection was high in these regions and surveillance data for children were scarce.Antibiotic stewardship policies to prevent infection and encourage appropriate treatment are needed in South-East Asia and the Western Pacific. Antimicrobial resistance occurs when bacteria are no longer susceptible to the drugs used for treatment.Klebsiella spp. with carbapenem resistance, resulting in extremely high rates of mortality.,,Extended-spectrum β-lactamases are enzymes that cause resistance to some of the most commonly used antibiotics,The World Health Organization (WHO) South-East Asia and Western Pacific Regions have over 4.3 billion of the world’s population of 7.7 billion, including two of the most populous countries with heavy consumption of antibiotics: China and India.Cochrane handbook for systematic reviews of interventions.We conducted the meta-analysis in accordance with the We made a comprehensive search, without language limitation, of online databases for articles published from 1 January 1940 to 30 June 2018 . Two resBox 1We searched online databases , electronic abstract databases and references in published articles. For the prevalence study we also searched the grey literature, including the websites of the World Health Organization and the United States Centers for Disease Control, surveillance systems related to antimicrobial resistance, dissertations, conference reports and country reports. When more information about studies was needed we contacted authors or website administrators.We used the following keywords:extended-spectrum beta-lactamase OR extended-spectrum beta-lactamase OR ESBL* OR ESBLs OR ESBL-producing* AND paediatric OR pediatric OR juvenile OR child OR children OR adolescence OR infant OR neonat* OR neonatal OR newborn OR nurseryAND Asia OR Asia Pacific OR South Asia OR The Western Pacific OR South-East Asia OR Australia OR Bangladesh OR Bhutan OR Brunei Darussalam OR Cambodia OR China OR Cook Islands OR Democratic People's Republic of Korea OR Fiji OR India OR Indonesia OR Japan OR Kiribati OR Lao People's Democratic Republic OR Malaysia OR Maldives OR Marshall Islands OR Federated States of Micronesia (Federated States of) OR Mongolia OR Myanmar OR Nauru OR Nepal OR New Zealand OR Niue OR Palau OR Papua New Guinea OR Philippines OR Republic of Korea OR Samoa OR Singapore OR Solomon Islands OR Sri Lanka OR Thailand OR Timor-Leste OR Tonga OR Tuvalu OR Vanuatu OR VietNam We included cohort, case–control and observational or cross-sectional studies. We defined the target population as children aged from birth to 21 years, according the American Academy of Paediatrics guidelines.The principal outcome measure was patients’ infection status, defined by whether specimens obtained tested positive or negative for infection with extended-spectrum β-lactamase-producing bacteria. We analysed infection status by risk sub-groups: medical history in the 3 months before the infection , exposure to invasive life support, antibiotic therapy and co-morbidities or underlying conditions. Other outcomes recorded were: hospital length of stay, mortality, persistent bacteraemia, antibiotic residence and duration of fever after antibiotic therapy.P < 0.05 was considered statistically significant. If studies provided median and interquartile range, we made estimates of the mean and standardized deviation (SD).For the meta-analysis we pooled the data on number of isolates (four studies) or patients with isolates (37 studies) using a Mantel–Haenszel random-effects model to determine the risk of infection with extended-spectrum β-lactamase-producing bacteria.2I statistic, which evaluates the consistency of study results. The cut-off for defining heterogeneity was 2I > 50%.We assessed the heterogeneity of the studies using the P < 0.1). We carried out meta-regression to explore each potential factor contributing to heterogeneity between studies, such as study location, design, duration and setting, and patients’ age and diagnosis, for all included studies reporting mortality and persistent bacteraemia. We used funnel plots with Egger regression test to assess publication bias , using the Meta and Metafor meta-analysis packages.We obtained data on the prevalence of extended-spectrum β-lactamase-associated infection from the same studies included in the meta-analysis. We also made a search for other data sources in the published and grey literature . We inclThe database search yielded 6665 articles. We removed 1089 duplicates and excluded a further 3046 studies after screening titles and abstracts. After assessing the full text of 577 studies, we excluded 537. Screening of reference lists and conference abstracts yielded no additional studies. In total, 40 studies were included in the meta-analysis . Three shttp://www.who.int/bulletin/volumes/96/7/18-225698). Overall, the 40 studies reported 46 960 bacterial isolates from 17 829 children providing samples. We pooled data from 2411 samples testing positive and 2874 testing negative for extended-spectrum β-lactamase-producing bacteria over the study period up to June 2018. The most common method of detection of bacterial phenotypes was agar disk diffusion in 32 studies. The study designs were 11 retrospective cohort studies, 14 prospective cohort studies, six observational studies, two cross-sectional studies and seven case–control studies. We found studies from 11 different countries and areas: Taiwan, China; India; Indonesia; Japan; Malaysia; Republic of Korea; Singapore; Sri Lanka; Thailand; and Viet Nam. In 15 studies the focus was specifically on neonates (< 28 days old), 15 studies were of age groups 0–21 years (excluding neonates), seven studies were of age 0–5 years (excluding neonates) and three studies did not specify the ages , hospitalization  or surgery , nosocomial infections , lower respiratory tract infections , sepsis  or recurrent urinary tract infections , vancomycin  and quinolones . Five studies reported that appropriate initiation of empirical antibiotics was protective, showing a pooled OR of infection of 0.29 . Other types of invasive life support were a risk, however. The OR for total parenteral nutrition was 3.8 . For mechanical ventilation the OR was 3.3  and for endotracheal intubation 2.1 . Central venous catheterization had an OR of 1.7  and lowest with cotrimoxazole . The ORs for resistance to tetracyclines and nitrofurantoin were not statistically significant  for patients with extended-spectrum β-lactamase-associated infection than those without such infection  than those without sepsis .59Eleven studies reported a pooled number of 188 deaths among 565 patients with extended-spectrum β-lactamase-associated infections compared with 86 deaths in 745 patients without these infections . Sensitivity analysis excluding small studies with samples less than 10 revealed that the funnel plots were consistently asymmetric . The sensitivity analysis showed that the data were not consistent with from the overall estimated ORs and similar trends were observed. This evaluation showed that a more restricted analysis of the data did not affect the magnitude, direction and the overall summary estimate.None of the factors we analysed by meta-regression were contributors to between-study heterogeneity. In the Newcastle-Ottawa analysis of risk of bias, we found that 60% (24 out of 40) of studies scored high on risk of bias and 40% were low risk ; Table 5The overall pooled prevalence of extended-spectrum β-lactamase in the studies included the meta-analysis combined with surveillance reports was 25.3%. The pooled prevalence from the studies in the meta-analysis was 39% among the 31 studies conducted in hospital settings and 31% in the seven studies conducted in community settings . Using data from other sources, we mapped population surveillance data from a total of 21 countries and areas in the South-East Asia and the Western Pacific Regions . The pooThis study revealed that the average combined prevalence of infection with extended-spectrum β-lactamase-producing bacteria among children in South-East Asia and the Western Pacific is high. Risk factors for infection included recent intensive care unit admission, hospitalization, surgery or antibiotic exposure, and co-existing bacteraemia, nosocomial infections, lower respiratory tract infections, sepsis or recurrent urinary tract infections. Infection was associated with higher mortality, higher morbidity and longer hospitalization.The prevalence of infection we found in South-East Asia and the Western Pacific countries are similar to those reported from other surveillance systems worldwide,As many of the studies we found were hospital-based our results support the need for resources and policies for control of nosocomial infection. A recently published modelling study showed that antibiotic use in hospital is a major driver for antimicrobial resistance in human infection compared with animal and environmental antibiotic exposures.,–Our meta-analysis showed that recent medical care, including intensive care unit stays, hospitalization, surgery and antibiotic therapy, was associated with increased risk of infection. These results suggest that children may acquire such infections during health care, especially when undergoing invasive procedures. Specifically, children who had exposure to third-generation cephalosporins, carbapenems and fluoroquinolones had three to four times greater risk for extended-spectrum β-lactamase-associated infection, which is similar to previous reports.,,Coexisting illnesses, including bacteraemia, nosocomial infection, lower respiratory tract infections, sepsis and recurrent urinary tract infections, were associated with increased risk of infection. These co-morbidities could be risk factors for use of invasive treatments such as a central venous catheterization, mechanical ventilation, intravenous nutrition or increased risk of interactions with health-care settings. In a two-centre case–control study of risk factors for infection with extended-spectrum β-lactamase-producers in children, multivariable analysis identified sepsis and neurological illnesses as potential risk factors, which supports our findings.Recent surgery and antibiotic prophylaxis were associated with extended-spectrum β-lactamase infection in our study. Others have shown that surgical antibiotic prophylaxis increases the risk for antimicrobial resistance and acquisition of infection.Our study found that initiation of appropriate empirical antibiotics was protective against extended-spectrum β-lactamase-associated infection, indicating the importance of thoughtful selection of antibiotics. The details of this finding warrant further study. The risk is especially high for critically ill patients requiring surgery or intensive care and who need antibiotics urgently before susceptibility has been established but who are also at increased risk for drug-resistant infections. Therefore, antibiotic stewardship programmes and guidelines in health-care facilities fill an important function. Furthermore, as studies in Asia have shown a high prevalence of easy access to unsupervised antibiotics within the community, more attention is needed to improving appropriate antibiotic use through training, education, policy and regulation outside of hospitals.Children infected with extended-spectrum β-lactamase-producers had significantly longer length of hospital stays (26 days) and required more intensive care unit days (29 days) than those without such infection. This leads to higher health-care costs,Mortality and persistent bacteraemia were three to four times higher for patients infected with extended-spectrum β-lactamase-associated infections than those without. This adds to the economic and social burden of these infections. Based on our meta-regression, the study location, study design, patient’s diagnosis, sex or intensive care unit stay did not influence mortality. This implies that worse outcomes may be directly attributable to the presence of extended-spectrum β-lactamase-associated infection. The severity of the diseases associated with these infections might also contribute to mortality risk, as the patients diagnosed with sepsis had higher risk of mortality than those without sepsis. However, we were unable to determine for each study whether other factors may have influenced outcomes because comprehensive information was not available.One of the strengths of our study was the comprehensive data collection strategy, which provided a high sample size and study power. Second, two different tools were used to assess for bias, which, together with risk factor and outcomes sensitivity analysis, strengthened the study’s validity and reliability. Third, we assessed previous antibiotic history with different antibiotic categories, providing a detailed insight into the link between antibiotic use and resistance. Fourth, we also conducted meta-regression to determine if other factors might have influenced treatment outcomes. This established association between patients’ mortality, length of stay and extended-spectrum β-lactamase infections.–There were several limitations to this study. The distribution of studies between locations was not uniform. Of the 48 Member States and areas in the South-East Asia and the Western Pacific Regions, we were able to find and extract data for the meta-analysis from 12 countries. For prevalence estimates we added surveillance data from 10 other countries and areas but we found data on 0–21-years-olds for only three countries with available paediatric data, which might underestimate the real situation among children. Moreover, although we made subgroup analyses, most of the pooled prevalence from selected studies were from hospital settings. Most of the surveillance sources reported only prevalence, without denominators and numerators. Nevertheless, the study provides a rough indication of the extent of extended-spectrum β-lactamase-associated infection and highlights the need for establishment of surveillance systems in these Regions. We can expect that within large Regions, rates of infection are unlikely to be homogenous, particularly where there are large urban and rural disparities. Among 40 studies, only seven were community based. This might have underestimated antibiotic resistance in the community. With the rising concern for community-acquired infections and reports of increased rates of faecal colonization with extended-spectrum β-lactamase-producing bacteria in healthy children, risk factors might not only arise from hospital influences but also from community exposure and international travel.Another limitation we faced was the lack of laboratory standardization for the identification of the extended-spectrum β-lactamase-producer phenotypes. Quality and standardization may vary between laboratories, although most followed Clinical and Laboratory Standards Institute guidelines. Sensitivity analyses found that use of different laboratory guidelines or test methods or the study year did not affect our results. All studies used phenotypic methods, as opposed to the gold standard through genotyping, with the majority using agar double-disk diffusion test, while a few studies used the Vitek® system . Thus, detection rates could be underestimated.We hope this study will provide important information for policy-makers who need to allocate resources to improve surveillance, monitor treatment outcomes, improve infection control in intensive care unit and surgery wards and develop policies for the use of empirical and prophylactic antibiotics. Knowledge of resistance rates can guide treatment recommendations. Countries without established antibiotic stewardship programmes should prioritize these activities, along with public education programmes. With very high burden of neonatal sepsis 0.42 million (39%) of the total 1.09 million deaths related with sepsis in these Regions,


Coronary artery disease (CAD) is commonly associated with abdominal aortic aneurysms (AAAs) in elderly patients. When severe CAD requiring coronary artery bypass grafting (CABG) is associated with an impending AAA in a high-risk patient, the options for the suitable timing of CABG and AAA repair strategy (one-stage or two-stage) are still being debated.An 87-year-old man with non-ST-segment elevation myocardial infarction and a giant abdominal aortic aneurysm was transferred to our centre. Coronary angiography revealed triple-vessel coronary disease, and computed tomography confirmed a giant infrarenal fusiform abdominal aortic aneurysm 9 cm in maximal diameter. We simultaneously performed endovascular aneurysm repair prior to on-pump beating-heart coronary artery bypass grafting. The postoperative course was uneventful, and the patient was discharged on the 15th postoperative day.Combined endovascular aneurysm repair and on-pump beating heart coronary artery bypass grafting in a one-stage operation is a promising strategy to improve therapeutic efficiency in octogenarians. More studies are needed to compare the efficacy and safety of one-stage and two-stage operations to treat concomitant coronary artery disease and aortovascular pathology in the high-risk octogenarian patients. The prevalence of AAA in patients with CAD has been reported to be approximately 8.4 % . Convers2An 87-year-old male patient was admitted to our centre from a local hospital with an initial diagnosis of non-ST-segment elevation myocardial infarction. The past medical history included controlled type II diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and chronic coronary artery disease. On physical examination, blood pressure was 120/85 mmHg, heart rate of 102 beats per minute and peripheral capillary oxygen saturation of 89 %. Besides, a large pulsatile mass was palpated around the umbilical area.On the diagnosis workup, the electrocardiogram showed sinus rhythm with Q and ST-segment depression in V2 to V5 and in aVL. Echocardiography revealed severe left ventricular systolic dysfunction (EF 28 %) with global left ventricular hypokinesis. The laboratory data were abnormal with high levels of creatine kinase-muscle/brain and troponin I at 68.7 U/L and 500 ng/mL, respectively. Coronary angiography showed that the coronary artery system was right-dominant. The lesion was complex with triple-vessel coronary disease: (1) 70–80 % stenosis of middle to distal left anterior descending (LAD) artery and 90 % stenosis of diagonal artery 1; (2) total occlusion of the distal left circumﬂex (LCX) artery with collateral blood flow from LAD; and (3) total occlusion of the right coronary artery (RCA) with collateral flow from septal LAD and the ipsilateral with collateral flow from the RCA . Apart fAccording to the SYNTAX score (46.5 points) calculated as described previously , these lUnder general endotracheal anaesthesia, EVAR was first carried out followed by CABG. Preoperative planning and sizing for EVAR was done on the basis of a three-dimension analysis using OsiriX software. Arterial access was achieved by exposing bilateral femoral arteries. The Endurant II AAA Stent Graft System  was successfully expanded without any leakage d. The to3In the treatment of patients with large or symptomatic AAA associated with critical CAD, although combined AAA repair and CABG in a one-stage operation has been sporadically reported, the optimal strategy and clinical outcomes are still debated, especially in elderly patients with multiple comorbidities and poor left ventricular function. A simultaneous surgery has some beneficial aspects, such as diminishing the risk of aneurysm rupture. Indeed, Paty et al. reported that 23 % of their patients had AAA rupture in the period after CABG . BlackboIn our case, aside from the serious clinical condition, non-ST-segment elevation myocardial infarction was confirmed and required CABG. The giant AAA 9 cm in diameter was impending rupture and needed to be prevented. We performed simultaneously EVAR and CABG because of the advantages of EVAR in high-risk patients . EVAR isTo conclude, although there were a lot of reports of octogenarian patients who have been successfully treated by simultaneous CABG and EVAR, the ideal strategy for this subgroup of patients is still debated and is a challenge for clinicians. Combined on-pump beating-heart CABG and EVAR is a promising way to improve the therapeutic efficiency. Nevertheless, further studies are needed to compare the efficacy and safety of one-stage and two-stage operations.No funding was received for this case report.Our Institute’s (Cardiovascular Center) representative was fully aware of this submission and this scientific activity including writing manuscript was approved by the Ethic Committee of Cho Ray hospital, where the patients were operated.Written informed consent was obtained from the patient for publication of this report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Tran Quyet Tien and Nguyen Thai An: Surgeon, the conception and design of the study, revising it critically for important intellectual content, final approval of the version to be submitted.Lam Thao Cuong and Ho Tat Bang: Acquisition, analysis and interpretation of data, drafting the article, final approval of the version to be submitted.This work does not apply as it is a case report of a patient who has given written consent and has been de-identified. It is therefore not prospective research involving human participantTien Quyet Tran, M.D., PhD.All authors attest that they meet the current ICMJE criteria for Authorship.Not commissioned, externally peer-reviewedThe authors declare that they have no competing interests.


MiR-33a has emerged as a critical regulator of lipid homeostasis in the liver. Genetic deficiency of miR-33a aggravates liver steatosis in a preclinical model of non-alcoholic fatty liver disease (NAFLD), and relative expression of miR-33a is increased in the livers of patients with non-alcoholic steatohepatitis (NASH). It was unknown whether miR-33a is detectable in the serum of patients with NAFLD. We sought to determine whether circulating miR-33a is associated with histological hepatic steatosis, inflammation, ballooning or fibrosis, and whether it could be used as a serum marker in patients with NAFLD/NASH.We analysed circulating miR-33a using quantitative PCR in 116 liver transplant recipients who underwent post-transplant protocol liver biopsy. Regression analysis was used to determine association of serum miR-33a with hepatic steatosis, inflammation, ballooning and fibrosis in liver biopsy.Liver graft steatosis and inflammation, but not ballooning or fibrosis, were significantly associated with serum miR-33a, dyslipidemia and insulin resistance markers on univariate analysis. Multivariate analysis showed that steatosis was independently associated with serum miR-33a, ALT, glycaemia and waist circumference, whereas inflammation was independently associated with miR-33a, HbA1 and serum triglyceride levels. Receiver operating characteristic analysis showed that exclusion of serum miR-33a from multivariate analysis resulted in non-significant reduction of prediction model accuracy of liver steatosis or inflammation.Our data indicate that circulating miR-33a is an independent predictor of liver steatosis and inflammation in patients after liver transplantation. Although statistically significant, its contribution to the accuracy of prediction model employing readily available clinical and biochemical variables was limited in our cohort. NASH has become a major cause of cirrhosis and hepatocellular carcinoma, and represents one of the most common indications for liver transplant in the United States . NASH deRecent reports have highlighted the critical role of microRNAs in regulation of hepatic steatosis. MicroRNAs negatively regulate expression of a wide variety of proteins involved in lipid metabolism, and thus post-transcriptionally modify lipolysis, lipogenesis and lipoprotein turnover . In addiNumerous studies have shown that miR-33 is a critical microRNA regulating metabolism of fatty acids and cholesterol by cooperating with transcription factors SREBP-1 and -2 (sterol-regulatory element-binding protein-1 and -2), respectively, and by regulating expression of genes of lipid and cholesterol synthesis  11]. Mi. Mi11]. Considering the crucial role of miR-33a in hepatic lipid metabolism and its increased presence in steatotic livers in humans, we hypothesized that miR-33a will be increased in the serum of patients with NAFLD and could be used as non-invasive diagnostic marker. We evaluated this hypothesis in a cohort of patients after liver transplant and used this cohort because of its well-defined demography, clinical data, meticulous follow-up and availability of protocol liver biopsy. Here we show that circulating miR-33a is significantly increased in serum of patients with fatty liver disease after liver transplantation, and that circulating miR-33a is independently associated with steatosis and lobular inflammation in liver biopsy.One hundred and sixteen liver transplant recipients undergoing protocol liver biopsy during standard post-transplant follow up between May 2015 and May 2017 were enrolled in this prospective study. We excluded patients with known or suspected alcohol abuse after liver transplantation (LTx), with HCV infection of the graft or with corticosteroids administration higher than 5 mg of prednisone per day. The most common indications for LTx in our cohort were biliary disorders , alcoholic liver disease  and HBV, autoimmune hepatitis and cryptogenic cirrhosis , the quantitative insulin-sensitivity check index (QUICKI) and the glomerular filtration rate (MDRD-GFR) were calculated using standard formulas. We also analysed clinical and anthropometric data, including age, body mass index (BMI), waist circumference, time from liver transplantation (LTx), presence of comorbidities such as hypertension, diabetes, and prescription medications . Next, we analysed clinical and anthropometric data of liver graft donors.Blood samples for miRNA relative expressions analysis were collected at the same time as blood samples for biochemical testing on same day when liver biopsy was performed. Serum was separated by centrifugation and stored at -80°C. MiRNAs were isolated from serum using miRCURY RNA isolation kit for biofluids (EXIQON). Before isolation, serum samples were spiked with control miRNA cel-miR-39-3p (QIAGEN), which served as control of quality of isolation and as reference gene. RNAcarrier—bacteriofage MS2 (Roche) was added for better yield.Liver biopsies were performed using the Menghini technique. Histologic sections of formalin-fixed, paraffin-embedded liver tissue were routinely stained according to the standard protocols. All samples were reviewed by an experienced histopathologist who was blinded to miRNA analysis. Liver biopsies were graded according to the scale published by Kleiner, where four morphological features related to NAFLD were semi-quantitatively appraised on light microscopy: steatosis, lobular inflammation, hepatocellular ballooning and fibrosis .One-way ANOVA or Mann-Whitney test, when appropriate, were used for comparison of continuous variables, and chi-square or Fisher’s exact test were used for comparison of proportions. To assess the role of miRNAs, clinical and demographic variables in clinical outcomes, stepwise logistic regression was used. Predicted probability values for clinical outcomes calculated in regression models were used to construct receiver operating characteristic curves. Goodness-of-fit statistics were assessed for all regression models. The level of significance was set at P less than 0.05. All P values were two sided. Statistical calculations were performed using SPSS Statistics Version 25 (IBM Corporation).2) in stable clinical condition participated in the study (60 men and 56 women). Median time from LTx was 2.2 years . Thirty-one patients had diabetes and 70 patients had hypertension. On average, plasma levels of aminotransferases were within normal range  increase of serum miR-33a, compared to subjects without steatosis  and C-reactive protein (CRP) . In addiMultivariate regression showed that miR-33a, glycaemia, waist circumference and ALT represent independent predictors of hepatic steatosis. Based on the Wald’s statistics, which assesses the relative contribution of each variable to the outcome in regression model, we hypothesized that the relative significance of miR-33a  in prediction of liver graft steatosis will be, at most, at par with clinical and laboratory parameters , glycaemia , ALT ) . To confUtilizing a similar approach for assessment of relative contribution of miR-33a to lobular inflammation in regression model, we found that the area under the curve (AUROC) for all three independent predictors  was 75.7%, whereas exclusion of miR-33a decreased accuracy to 74.7% . Taken tPNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphism in corresponding donors, higher BMI, higher triglycerides plasma concentration and diabetes mellitus . Se. Se11]. Although we identified miR-33a as independent predictor of liver graft steatosis and inflammation, it needs to be emphasized that statistical significance does not always imply clinical relevance. Using ROC analysis we showed only limited contribution of miR-33a to prediction modelling of steatosis and lobular inflammation in the context of other independent clinical or demographic predictors. This finding of limited clinical relevance is consistent with previously published reports, that showed that AUROC of microRNA (namely miR-34a miR-122) in the diagnostics of lipid accumulation or liver inflammation was between 0.6–0.8 . Not onlThe inherent drawback of using miRNAs as non-invasive markers of liver disease relies in their mechanism of activation, which is usually dependent upon gene or metabolic pathways they are part of. If, as it is often in the case of NAFLD, those genes are involved in glucose or lipid regulation, then readily available laboratory markers of insulin resistance or dyslipidemia will provide similar diagnostic information and therefore it would be of no surprise that adding the corresponding miRNA does not further contribute to the diagnostic model accuracy.We used a cohort of liver transplant recipients for our study because we believe that these represent appropriate in vivo model of liver steatosis and steatohepatitis demonstrating most of the epidemiologic and genetic risks described in general population ,16,17. WNevertheless it is necessary to keep in mind that transplanted patients are specific cohort, due to immunosuppression including steroids, .Data are given as N (%) or median (1(DOCX)Click here for additional data file.S2 Tablest - 3rd quartile).Data are given as N (%) or median (1(DOCX)Click here for additional data file.S3 Tablest - 3rd quartile).Data are given as N (%) or median (1(DOCX)Click here for additional data file.S1 FigBiliary cirrhosis was indication for LTx in 33 patients (28.5%), alcoholic liver disease in 28 (24.1%), HBV, autoimmune and cryptogenic in 8 patients each (7%), HCV in 4 patients (3.4%), NASH in 1 patient (0.9%) and other diagnoses in 26 patients (22.4%).(JPG)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.