As the availability of prescription opioids decreases and the availability of heroin increases, some prescription opioid users are transitioning to heroin. This study seeks to explore factors associated with respondents’ transition from prescription opioid use to heroin.n = 20) were conducted with buprenorphine patients in an opioid treatment program. Respondents were predominantly White (n = 13) and male (n = 13), with a range of treatment tenure (4 days to 2 years).In-depth, semi-structured qualitative interviews (n = 15) initiated opioid use with either licit (n = 8) or illicit (n = 7) prescription opioids . Of these respondents, all but two transitioned from prescription opioids to heroin (n = 13). For those respondents who transitioned to heroin, most initiated heroin use intranasally (n = 12), after using prescription opioids in the same manner (n = 9), but before using heroin intravenously (n = 9). Respondents attributed this transition between substances to common explanations, such as “it’s cheaper” and “the same thing as pills.” However, respondents also dispel these myths by describing: 1) heroin quality is always uncertain, often resulting in spending more money over time; 2) dramatic increases in tolerance, resulting in spending more money over time and transitioning to intravenous use; 3) more severe withdrawal symptoms, especially when respondents transitioned to intravenous use.A vast majority of respondents in this study (Understanding how route of administration and common myths shape key transition points for opioid users will allow practitioners to develop effective harm reduction and prevention materials that target individuals already using prescription opioids. With greater than 10 million individuals in the US reporting non-medical use of prescription opioids (NMPOs) in 2014 , but simResearch during the last decade has established that individuals who abuse prescription opioids, especially those with a physiological dependence, may shift to heroin use, particularly when they already inhale or inject prescription opioids –17. SeveQualitative respondents in some of these studies have reported that the greater accessibility of heroin, and the relatively low cost compared to prescription opioids (because of their scarcity), facilitated their initiation to heroin use , 16, 17.n = 20) were conducted with buprenorphine patients in an opioid treatment program in Delaware. Participants were recruited to ensure demographic and experiential diversity, with specific attention paid to recruiting participants along racial, ethnic, and gender subsamples that roughly mirrored those of the larger clinic population. Although 20 interviews were completed, only those respondents who reported initiating their opioid use with prescription opioids were included in this analysis (n = 15). Overall, these respondents were predominately white (n = 9) and male (n = 10), with only a few identifying as Hispanic (n = 3). The age of respondents ranged from 23 to 60, with an average age of 36. Respondents provided informed consent, and all research activities were approved by the University of Delaware Institutional Review Board.In-depth, semi-structured interviews , but averaged approximately 45 min. Interviews explored respondents’ substance use histories; treatment history and experience; issues encountered accessing buprenorphine treatment; family, friends’, and employer attitudes toward buprenorphine; criminal justice issues related to buprenorphine; plans to taper off buprenorphine; and, advice for future buprenorphine patients.Qualitative data collection and analysis occurred simultaneously, allowing previously collected data to inform ongoing data collection and ensure saturation. Interviews were audio recorded and carefully transcribed to ensure accuracy. Following transcription, all participant names were replaced with pseudonyms. Interview transcripts were analyzed using an inductive coding scheme approach with ATLAS.ti qualitative analysis software. A primary coding scheme was developed based on the conceptual and thematic areas targeted in the interview guide. Within these primary level codes, the researchers inductively developed secondary level codes that were dependent upon narratives of the respondents. While the larger focus of the interviews was on buprenorphine respondents’ experiences in a traditional opioid treatment program that largely served methadone patients, the data presented here emerged organically when respondents’ substance use history was systematically analyzed.n = 8) received their first opioid through a licit prescription for an illness or injury. Of the 15 respondents who initiated opioid use with prescription opioids, all but two eventually began using heroin. However, since the observation time between participants’ initiation of opioid use and the time of the interview were different, caution should be used when interpreting the significance of these two cases. Nine of the 13 respondents who eventually moved to heroin were using intravenously at the time of treatment entry. It should be noted, however, that none of these 15 respondents ever, at any point, injected prescription opioids during their years of opioid use—only heroin.The respondents in this study followed similar opioid use trajectories. As shown in Table The respondents who initiated opioid use with prescription pain relievers had a history of opioid use ranging from 2 to 16 years  responded:Luke  was similarly influenced by someone in his substance user network who informed him that heroin was less expensive than the oxycodone he was using. When Luke first began taking 30 mg pills (often referred to as “Roxy’s” for Roxicodone), he would break them into pieces and use quarters of the single pill throughout the day. As his tolerance grew and his addiction intensified, he began to use more of the pill, more often during the day, until he was using multiple pills per day. As Luke used more pills, he had difficulty keeping up with the cost, so he decided to try heroin when an acquaintance told him it was cheaper.I was scared to death because I kept hearing people overdosing, and I said I would never do that, never, never, never, but there I was. My girlfriend, she’s like, “You’re paying $20 for a Perc 30, common, $20 you can get 6 bags of dope, they’re $5 a damn piece, and that $5 bag equals the $20 you’re paying for the Perc 30. That one bag equals that one pill.” And that’s what changed my mind. It tempted me, so I sniffed the one bag and within a half hour I was feeling good, I was able to move around, I was able to do my chores, whatever.The phenomenon of prescription opioid users transitioning to heroin due to the scarcity and rising cost of opioid pills is well-documented in the literature  was, and he was like it’s just like a Perc and it’s cheaper. First I was like “No! I’m gonna die!”, and this and that. “I’m not shooting up!” Then he said, “no, you’re not going to overdose, it feels just like a Perc”. And I was like, “why? Have you done it?”, and he was like, “yea, I’ve tried it a couple times.” And I was like, “fine, let’s just try it.” So that’s how that started… But I mean, also because pretty much to even get in here [treatment program], like the shooters get more help and quicker than the sniffers do. So, like you at least have to have a track mark, so I’m like I might as well just try it, like there’s no other way.It is not surprising that these same informal networks also supplied information and advice about treatment options. By the time Julie transitioned to shooting heroin, other opioid users in her social network had informed her about the priority intake policies at several treatment clinics in the area. While this was not the sole reason for Julie’s change in route of administration, the fact that intravenous users are accepted for intake into the clinics more quickly contributed to her rationalization that shooting heroin would be okay, and perhaps even useful.It is important to note that this openness was not devoid of perceptions of risk. Tami was quite scared to use heroin intravenously, even believing that there was an imminent possibility she could overdose from a single use. This fear was shared by other respondents in the study, like Julie , who didn’t use heroin until she was talked into it by someone very close to her:Other respondents actually used the same cost-benefit reasoning that led them from prescription opioids to heroin, in their decision to move from sniffing heroin to shooting heroin. Eric, began using heroin because it was a cheaper alternative to his prescription opioids, but noted that his tolerance increased at a much faster rate once he transitioned to heroin. His rationale for transitioning from sniffing heroin to shooting heroin was also a way to save money, because shooting heroin is a more efficient route of administration with a greater bioavailability.Unfortunately for Eric, his life started unraveling at a much faster pace after his transition to heroin, and his switch to intravenous administration. He eventually lost his job, apartment, and custody of his two sons; he served 1 year in prison for theft and is now a convicted felon. Eric had never used an opioid before September 2012; by January 2013, he had transitioned to heroin. He entered his first detox facility in May 2013 and was incarcerated by April 2014.Respondent:It was definitely, I’m still kinda shocked. Like wow, 6–7 months? And like all these years of taking Percs and like, I could go for a whole month taking them every day and just be fine. And I just never really thought that I was going to get addicted that FAST, and then to have the withdrawal symptoms like that, and you really do have to get up and it’s hard, to just stop. The way it completely takes over you, I’m still kind of like wow, how did this happen?? Like me and my husband, like especially the couple weeks prior to getting help, we’ve been talking about how we have to get help. And you know this whole first week together, you know getting help, like we even say, can you IMAGINE people who have been doing it for years? Like if we felt like we’re feeling, you know? And it’s only been like 6–7 months. Can you imagine? Like it’s already taken a toll on us, and our lives.Eric was not the only patient that noted experiencing significant, and rapid, negative effects to his life from using heroin intravenously. Julie had a particularly poignant dialogue during her interview, where she reflected with utter disbelief about how quickly the transition from pills to heroin, and from sniffing to shooting, occurred.the same thing as pills.” Besides the (presumed) difference in cost, users would have no reason to transition to heroin unless they believed pills and heroin where interchangeable. According to the respondents in this study, the notion of interchangeability is perhaps the most critical piece of misinformation being exchanged within substance-using networks. When asked how she would compare withdrawal experiences from prescription opioids and from heroin, Tami explained:Respondent:From the heroin? How can I compare it? The withdrawal from the heroin and intravenous use is WORSE. It is deathly, deathly worse. I swear it is… There’s also a difference between the withdrawal from sniffing and a withdrawal from intravenous. There’s two different withdrawals from that too… It is the same set, but it’s more intense, and it comes on stronger. Like, I can wake up and be instantly sick as soon as I got out of bed. I’d be throwing up and using the bathroom in my pants, and all of that. Compared to if I sniffed, I would have a few hours before I got like that. Or a day even. But intravenous use, because it goes right into your vein it brings it on stronger, the withdrawal is worse.Overall, respondents in this study maintained dependence on a fairly consistent level of prescription pills for a majority of their use periods. The 13 respondents in this study that initiated opioid use with prescription pills and later transitioned to heroin had an average of 9.2 years of opioid use in their lifetime – but only an average of 2.1 years of heroin use after making the transition. The most consistent reason respondents gave for transitioning from prescription pills to heroin was that they believed “it was Over the course of the previous decade, existing literature has identified prescription opioid misuse and alternate forms of route of administration as potential precursors to future heroin use –17. Amonhow participants use opioids may be just as important as what opioids they report using. This is especially important to consider beyond the normative emphasis placed on injection drug use, given its association with other public health risk factors such as contraction of HIV or Hepatitis C.Consistent with previous qualitative analyses , 16, then = 54) of participants who had reported previous or current use of prescription opioids, but at the time of participating had a primary drug of heroin, 94% reported using heroin because prescription opioids were more expensive and harder to obtain. While this study initially found respondents discussing similar reasons for transitioning to heroin, when asked to reflect upon if those reasons remained true throughout their heroin use, respondents indicated that they were false in the long run.In addition to developing a greater understanding of the role of route of administration in prescription opioid to heroin transitions, this study also used patient narratives to debunk existing myths that have been promulgated widely in opioid use networks. Findings from this study expand on the literature in this area, which largely agrees that participants become convinced that heroin is the ‘same’ as prescription opioids, while also being cheaper and more easily available . In factOther qualitative studies have focused on the route of administration transitions of youths with opioid use disorders, finding that this group largely attributed their transition to injection use to individual tolerance, cost, and shifting drug markets – findings that are consistent with those presented in this study . AdditioThis study had several limitations. First, the data were collected from a purposive sample of participants who were receiving buprenorphine in a treatment clinic setting that primarily dispensed methadone. There are several pharmacotherapy-based settings in which individuals with opioid use disorder can access treatment, as well as many non-medication centered programs that offer abstinence-based treatment. It is possible that these buprenorphine respondents do not represent the experiences of participants entering other types of treatment for opioid use disorder. Second, there are many reasons individuals decide to access treatment at a given time , which makes this population selective, given that all of the participants were recruited into the study during their most recent treatment experience. Third, qualitative data collection centered around retrospective lines of inquiry may be subject to recall bias since some of the events and situations that were discussed may have occurred years prior to the interview.how route of administration and transitions from prescription opioids to heroin occur, and 2) how myths surrounding the perceived benefits of transitioning from prescription opioids to heroin are debunked over time as individuals continue using heroin. Although preliminary, both of these findings point to the importance of generating harm reduction interventions that target individuals who may be at risk of transitioning, or have recently transitioned, to heroin.With the increased public attention on opioid use disorders, as well as concern surrounding a dramatic rise in opioid-related overdose deaths in recent years, understanding the association between prescription opioid use and transitioning to heroin has been at the forefront of opioid-related research. This study contributes two major findings to the existing body of literature in this area, namely: 1) a specific and nuanced understanding of


MET copy number (MET-CN) in patients with non-small cell lung cancer (NSCLC), we retrospectively reviewed clinical and pathologic data of NSCLC patients whose tumors were assessed for MET-CN using fluorescence in situ hybridization (FISH). We correlated MET-CN status with patient overall survival (OS) and optimized MET-FISH reporting criteria. The study group included 384 patients with NSCLC of which 88% were adenocarcinoma and 55.7% of patients had distant metastases. There were 170 patients with stages I-III and 214 patients with stage IV disease. Based on the MET-CN and MET/CEP7 ratio the patients were classified into 3 categories: MET-amplification (METamp): MET/CEP7 ≥ 2 or MET-CN ≥ 5; MET-CN-gain (METcng): MET-CN ≥ 4 to < 5; and MET-negative (METneg): MET-CN < 4. METamp was associated with high fatality (P=.036) and stage IV tumors (P=.038). In patients with stages I-III NSCLC, patients in the METamp category had the shortest OS (P=.015) and more often developed distant metastases within 1 year (P=.004). In patients with stage IV tumors, METamp did not further impact the OS. Patients in the METcng category had the longest OS (P=.053). Multivariate analysis confirmed METamp to be an independent high-risk factor  and predicted earlier progression to distant metastasis . In conclusion, we suggest that the MET-FISH criteria presented optimizes risk stratification by defining 3 categories of NSCLC patients. METamp is an independent risk factor predicting early distant metastasis and patients with METcng could represent a lower-risk group.To investigate the prognostic impact of  MET) which resides on chromosome 7q31, can be detected conveniently by using fluorescence in situ hybridization (FISH). MET amplification (METamp) has been associated with shorter overall survival (OS) in patients with non-small cell lung cancer (NSCLC) ..MET-CN aP =.321). Groups 4 and 5 also had similar OS . Patients in Groups 1 and 2 had markedly longer median OS than did patients in Groups 4 and 5. Interestingly, patients in Group 3 had significantly longer median OS than patients in any other group   Figure .MET-CN cutoff of 5 copies and a MET/CEP7 ratio cutoff of 2.0. These optimized MET-FISH reporting categories were as follows:METamp: (A) MET/CEP7 ratio ≥ 2.0, or (B) MET-CN ≥ 5, or (C) MET/CEP7 ratio < 2.0 but MET-CN ≥ 20 or MET signal clusters in more than10% of tumor cells.– MET-CN-gain (METcng): MET/CEP7 ratio < 2.0 and MET-CN ≥ 4 to < 5.– METneg: MET/CEP7 ratio < 2.0 and MET-CN < 4.– Because our OS data for patients with stages I-III disease were consistent with those of reported previously in a large study , we nextWe reclassified all cases into these 3 categories for further analyses of OS and risk stratification Figure .MET-CN in the overall study cohort was 3.1 copies per cell . The mean MET/CEP7 ratio was 1.15 . The mean MET-CN and mean MET/CEP7 ratio were significantly higher in patients with stage IV NSCLC than in patients with stages I-III disease   patients were categorized as having METamp.The mean ctively) . Using tMETneg group, 10 (5.9%) in the METcng group, and 7 (4.1%) in the METamp group. Of the 214 patients with stage IV disease, 185 (86.4%) were in the METneg group and 7 (3.3%) in the METcng group. We determined that 22 (10.3%) patients with stage IV NSCLC had METamp, a significantly higher rate than that found in patients with stages I-III disease (P =.038), indicating that METamp was highly associated with advanced disease stage  were in the P =.14), indicating that MET overexpression is not associated significantly with disease stage  (MET-FISH and the MET-IHC was 44.8% (P =.11) (MET overexpression as assessed by immunohistochemistry (IHC) was available in 202 of 384 (52.6%) patients, including 92 of 170 (54.1%) patients with stages I-III and 110 of 214 (51.4%) patients with stage IV disease. MET overexpression was found in 51 (55.4%) patients in stages I-III and 73 (66.4%) patients with stage IV (se stage . In addi(P =.28) . The ove(P =.11) .P =.18), sex (P =.58), or race/ethnicity (P =.45). As expected, longer OS was highly associated with early-stage (I-III) disease (P <.001) and with adenocarcinoma (P <.001)  .MET-FISH reporting criteria, the median OS durations of early-stage patients with METamp, METcng, and METneg were 28.1, 134.4, and 51.6 months, respectively. Patients with METamp had significantly shorter OS than did patients with METneg (P =.036), and patients with METcng had longer OS than did patients with METneg, although the difference was not statistically significant (P =.109)  Figure , Table 3MET-CN status showed no statistically significant association with OS . This pattern was similar to that observed in patients with stages I-III disease.In patients with stage IV tumors,  Figures , Table 4MET-CN and disease metastases in patients with stages I-III NSCLC. The 7 patients with METamp tumors had a significantly shorter median time to distant metastasis (11.6 months) than did patients with METneg  or METcng (37.0 months) tumors . Patients with stage III tumors showed a higher risk for distant metastases  and for shorter OS  than did patients with stage I disease. Patients with METamp tumors had significantly shorter OS than did patients with METneg tumors . In addition, METamp was found to be highly associated with distant metastases  . We further assessed the potential clinical impact of MET overexpression in patients with different disease stages. In 92 patients with stage I-III disease, the median OS was 51.6 months in those with tumors with normal MET expression (n = 41) versus 54.9 months in patients with tumors with MET overexpression (n = 51) (P =.97). In 110 patients with stage IV disease, the median OS was 16.3 months in those with tumors that showed normal MET expression (n = 37) versus 20.4 months in those patients with tumors with MET overexpression (n = 73) (P =.67)  . Our datMET-CN status in 384 NSCLC patients with various disease stages and identified associations between MET-CN and clinical outcome. To resolve the conflicting MET-FISH reporting criteria in the literature, we stratified our patient cohort into 5 groups based on MET-CN and MET/CEP7 ratio and identified associations between these groups and outcomes. We focused initially on patients with stage I-III tumors because METamp has been reported to be associated with stage IV tumors [MET-FISH reporting criteria by integrating MET-CN and MET/CEP7 ratio and reclassifying the patients into 3 groups: METamp, METcng, and METneg. These new, optimized criteria merged groups 4 and 5 (MET-CN ≥ 5 and MET/CEP7 ratio ≥ 2.0) into one group, METamp, because they had similar OS (METcng (MET/CEP7 ratio < 2.0 and MET-CN ≥ 4 to < 5) had markedly better OS than did patients in the other groups, suggesting that patients with METcng constitute a distinct group of NSCLC patients. We also found that patients with METamp had a higher risk of distant metastasis than did patients in the other groups.In this study, we evaluated data on V tumors . On the milar OS . These rMET-FISH reporting criteria we suggest, the overall frequency of METamp in this study cohort was about 8%. We noted that METamp was significantly more common in patients with stage IV disease than in patients without distant metastases. We confirmed that METamp was an independent risk factor for poor OS in patients with early-stage (I-III) NSCLC , consistent with results reported previously [METamp and stage I-III disease in this study cohort developed distant metastases within 1 year of diagnosis, indicating that METamp status predicts early distant metastases in patients with stages I-III NSCLC. Although 34 patients in the stage I-III disease group were positive for EGFR mutation, when this subset was compared with those who had no EGFR mutations, there was no significant impact observed on OS or progression to distant metastasis.According to the MET-CN status and its clinical implications in patients with stage IV NSCLC [METamp was highly associated with stage IV NSCLC, but did not further negatively impact clinical outcomes when compared with the METneg category for patients with the same disease stage. However, we found that patients with stage IV disease and METcng had much longer OS durations than did those with either METneg or METamp .Only limited clinical data have been published on IV NSCLC , 6, 16. METcng category identified in this cohort likely represents a distinct group of NSCLC patients, similar to that identified by Cappuzzo et al. [MET-CN ≥ 4 to < 5 as METneg and for that reason did not provide full clinical data for all patients. We speculate that the METcng category may represent patients with multiple polysomies e.g. near-tetrasomies as indicated by the copy numbers. Most of the 17 METcng patients in this cohort, who presumably had near-tetrasomy of chromosome 7, also showed evidence of having near-tetrasomies of chromosomes 2 (by ALK-FISH), 6 (by ROS1-FISH), or 10 (by RET-FISH) (data not shown). METcng coinciding with CN gains of ALK, ROS1, and RET likely resulted from genome-wide polysomies, particularly near-tetraploidy. Similar findings have been reported in a study of 47 patients with EGFR-negative lung cancer, in which 13 patients with polysomy 7 showed improved progression-free survival [METcng samples. SNP array data showed an overall good concordance with FISH, and the normalized genomic profiles in cases with METcng showed significantly lower genomic copy number complexity comparing the METneg and METamp groups. Although our microarray sample number was small, such METcng cases with a low frequency of somatic copy number alterations (SCNAs) [The o et al. , althougsurvival . To furtMETcng with MET inhibitors. Several clinical trials have failed to show any positive effect of MET inhibitors on patient survival. We speculate that these studies may have inaccurately identified patients with METcng as having METamp. For example, in one phase II study of 37 MET-positive patients [MET positivity was defined as MET-CN ≥ 4 in over 40% of cells; only 3 of the 37 patients with a MET/CEP7 ratio > 2.0 would have been interpreted as having METamp using the criteria we suggest in this study. Similarly, in a phase III study, only 4 of 54 patients had a MET/CEP7 ratio > 2.0 [METcng, not “real” METamp, and that this may explain the poorer response among these patients to MET inhibitors. Our results highlight the clinical importance of accurate MET-CN assessment using standardized and optimized reporting criteria in determining eligibility for clinical trials of MET inhibitors.On the basis of these observations, we argue against treating patients who have patients , MET posio > 2.0 . We specMET-CN at the borderline of METneg and METcng (3.8-3.9) or of METcng and METamp (4.8-4.9) can be challenging for risk stratification, as some of these results could be explained by tumor heterogeneity which are not uncommon in many cancers. However, in such cases, the overall estimated copy numbers i.e. by FISH for the assessment of oncogene amplifications are often underestimated [METamp in this study, the results are in line with what have been reported. In addition, using our suggested reporting criteria, those cases with tumor cells with clustering MET-FISH signals in > 10% cells would be considered to be positive and this can be considered as alternative method to address tumor heterogeneity to at least some degree. To further address tumor heterogeneity, we recommend reflex testing by repeating FISH or reflex testing using alternative assays, such as chromogenic in situ hybridization [MET-FISH cannot assess genome-wide SCNAs that are often associated with treatment resistance or disease progression in NSCLS, and an integrated genomic approach to accurately assess SCNAs could be utilized in the clinical settings in near future [Cases with a stimated . Using tdization , microardization , 29, comdization . We are METamp did have the higher number of cases with MET overexpression compared with the METneg and METcng subgroups (HER2 amplification and HER2 overexpression reported previously [MET-CN and MET expression observed in this study was low (~ 45%) which was consistent with what has been reported by others [MET-CN by FISH [Over half of the patients in the current cohort were also assessed for MET expression status by IHC. Our results show that MET overexpression were not associated with disease stages, although patients with ubgroups . Unlike eviously  the overy others . Similary others  and othey others . Our daty others  and that by FISH .MET-FISH reporting criteria that are useful for stratifying risk in patients with all stages and histological types of NSCLC. Our results indicated that METamp is strongly associated with stage IV tumors and that MET-FISH testing can identify patients who are eligible for treatment with MET inhibitors [METamp is an independent predictor of poorer prognosis in patients with stages I-III NSCLC. METamp is also a reliable predictor of distant metastases in patients with early stages NSCLC and, such patients may be candidates for more intensive treatments, such as combination therapy using MET inhibitors after surgery. Finally, we found that METcng could represent an independent prognostic group of patients with NSCLC; however, more data are needed to confirm this observation.In conclusion, we suggest that the optimized hibitors . FurtherMET using FISH between February 1, 2010 and December 31, 2015 at MD Anderson Cancer Center. All patients diagnosed with NSCLC for whose detailed clinicopathologic data are available were included. Patients with ALK receptor tyrosine kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), or ret proto-oncogene (RET) gene rearrangements were excluded from the study. Clinical disease stage for all patients was determined using the National Comprehensive Cancer Network staging system for NSCLC [We retrospectively reviewed the records of all patients with NSCLC who had been tested for or NSCLC . This stMET-copy-number (MET-CN) status was assessed using a dual-color FISH probe set  targeting MET and CEP7on formalin-fixed, paraffin-embedded tissue sections from tumor specimens following established standard laboratory procedures. MET-CN and the number of CEP7 per nucleus were scored in 60 cells and the mean MET/CEP7 ratio was calculated for each specimen. A subset of FFPE tissue specimens from at least 20 normal individuals was included to establish normal cutoff values following laboratory standard procedures (e.g. chromosome 7 aneuploidy such as monosomy or trisomy/tetrasomy/polysomy 7). The initial reporting criteria used at our institution during the study period, which we designate here as “historical” MET-FISH reporting criteria, classified cases into two categories, METamp and MET-negative (METneg), with a cutoff of MET/CEP7 ratio of 2.0. A sample was considered to have METamp if the mean MET/CEP7 ratio was ≥ 2.0 or if the MET/CEP7 ratio was < 2.0 but the MET-CN was ≥ 20 copies/cell or MET signal clusters were seen in more than10% of tumor cells [or cells .MET immunohistochemical staining (MET-IHC) was evaluated using a Benchmark Ultra Autostainer  with anti-total c-MET (SP44) rabbit monoclonal primary antibody , following the manufacturer’s instructions. Staining was scored by determining the percentage of cells showing weak (1+), moderate (2+), or strong (3+) membranous staining. MET overexpression was considered as positive if ≥ 50% of tumor cells showing cellular membrane staining at an intensity of “2+” or “3+” . ScoringMET-CN, were summarized using frequencies, percentages, and distributions. Categorical variables were compared using chi-square and Fisher exact tests, and continuous variables were compared using the Student t test. OS was calculated from the date of first diagnosis to the date of last follow-up or death of the patient. The log-rank test and Kaplan-Meier curves were employed to compare OS between subgroups. GraphPad Prism software version 6  was used for the survival analyses. Multivariable analyses, including Cox proportional hazards regression analysis, were performed using SPSS software version 9.3 . All tests were 2-sided when appropriate, and differences were considered significant at P <.05.Patient and tumor characteristics, including demographics, tumor type, and


Mechanically ventilated, intubated patients are at increased risk for tracheal colonization with bacterial pathogens that may progress to heavy bacterial colonization, ventilator-associated tracheobronchitis (VAT), and/or ventilator-associated pneumonia (VAP). Previous studies report that 10 to 30 % of patients with VAT progress to VAP, resulting in increased morbidity and significant acute and chronic healthcare costs. Several natural history studies, randomized, controlled trials, and a meta-analysis have reported antibiotic treatment for VAT can reduce VAP, ventilator days, length of intensive care unit (ICU) stay, and patient morbidity and mortality. We discuss early diagnostic criteria, etiologic agents, and benefits of initiating, early, appropriate intravenous or aerosolized antibiotic(s) to treat VAT and reduce VAP, to improve patient outcomes by reducing lung damage, length of ICU stay, and healthcare costs. VAT Pseudomonas aeruginosa isolates with toxins or other multi-drug resistant (MDR) pathogens that require early, effective, intravenous or aerosolized antibiotic therapy, as well as re-evaluation of non-responders to antibiotic therapy.VAT is an unappreciated but important early clinical condition in ventilated patients which has been linked to VAP, resulting in significant patient morbidity and mortality –7. The in = 22) versus no therapy (n = 36). The antibiotic-treated group had more mechanical ventilation-free days , reduced VAP , and significantly lower ICU mortality .Several studies have compared outcomes of ventilated patients, focusing on increased ventilator days and length of ICU stay for VAT and VAP patients. In addition, numerous studies have demonstrated improved patient outcomes in VAT patients treated with appropriate antibiotics –9. NseirClostridium difficile colitis resulting from intravenous antibiotic therapy. Of note, Palmer and Smaldone [p < 0.0001) and 14 out of 16 patients were cured (p < 0.001).Aerosolized antibiotic therapy for VAT and VAP has attracted increased interest. It is administered using an in-line nebulizer and has the advantage over intravenous therapy of being able to deliver a higher concentration of antibiotics into all parts of the lung, which can decrease bacterial lung burden, pulmonary damage and associated complications, as well as Smaldone  reportedSerial endotracheal aspirate (ETA) surveillance samples can help clinicians identify numbers of pathogens and the antibiotic sensitivity profile needed to initiate earlier appropriate antibiotic therapy to decrease colonization, VAT, and VAP –8. In “tDepuydt and coworkers  demonstrVentilated ICU patients are invariably complicated, often elderly, critically ill patients with underlying acute and or chronic diseases or post-surgery and who are at increased risk for VARI, an “infection vortex” with complications such as lung bacterial burden, damage that increases host debility, and delirium or post traumatic stress disorder, which may linger for months or years, resulting in hospital readmissions and enormous healthcare costs –14. For Staphylococcus aureus or P. aeruginosa, which produce toxins, or MDR Gram-negative bacterial pathogens. Ventilated patients should undergo careful monitoring to assess the need for early antibiotic therapy and so the endotracheal tube is removed as soon as possible to reduce leakage around the endotracheal tube cuff or biofilm emboli from the endotracheal tube lumen. Careful monitoring is also needed to assess the impact of early antibiotic therapy, the use of sedation vacations, and “walk to wean” programs for better patient outcomes and reduced hospital stay and associated healthcare costs. In 1895, Sir William Osler MD, an expert on pneumonia, said “Remember how much you don’t know”. Today, he might add “Remember how much your care team know and can apply.”We recommend use of VAP prevention strategies with a focus on earlier diagnosis and use of pre-emptive, appropriate antibiotic therapy based on clinical signs and microbiologic evidence of heavy endotracheal colonization, VAT, or VAP. This can be done by using serial lung surveillance cultures to identify bacterial pathogens and antibiotic sensitivity profiles, assessing levels of bacterial colonization for the presence of more virulent strains, such as


Monoclonal antibodies can be seen as valuable tools for many aspects of basic as well as applied sciences. In the case of MET/HGFR, they allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing structure–function relationships. Antibodies directed against MET extracellular domain were found to be full or partial receptor agonists or antagonists. The agonists can mimic the effects of the different isoforms of the natural ligand, but with the advantage of being more stable than the latter. Thus, some agonist antibodies promote all the biological responses triggered by MET activation, including motility, proliferation, morphogenesis, and protection from apoptosis, while others can induce only a migratory response. On the other hand, antagonists can inhibit MET-driven biological functions either by competing with the ligand or by removing the receptor from the cell surface. Since MET/HGFR is often over-expressed and/or aberrantly activated in tumors, monoclonal antibodies can be used as probes for MET detection or as “bullets” to target MET-expressing tumor cells, thus pointing to their use in diagnosis and therapy. Moreover, because of their modular structure they can be easily engineered through molecular biology technologies; this is extremely useful in case of a therapeutic use in humans . One of MET, the tyrosine kinase receptor of HGF, is another potential target in different types of solid and hematological neoplasms, such as colorectal carcinoma , glioblai.e., promoting epithelial mesenchymal transition, which was then found to be the same molecule [MET and its physiological ligand, hepatocyte growth factor/scatter factor (HGF), were discovered in the 1980s as a result of three independent lines of research, reflecting the pleiotropism of this receptor/ligand couple. MET was first identified in a rearranged tumorigenic form, giving rise to the TPR-MET fusion protein , and opemolecule ,13 and tmolecule ,15. The molecule , which cmolecule , and to molecule . Moreovemolecule . The manmolecule ,21,22.The same biological responses that are strictly regulated by HGF in MET-expressing cells in normal or repairing physiological settings can be subverted and become responsible for tumor development and metastasis ,23. AbnoWhile in the case of some tumors MET-mediated cellular activities may be independent from the ligand, all the physiological activities mediated by this receptor are strictly dependent on and regulated by HGF stimulation. Thus, depending on the target system considered, MET activation may trigger detrimental responses (uncontrolled proliferation and tissue invasion in cancer) or beneficial effects . Antibodies are reagents of high specificity and affinity and can be viewed as alternative ligands of the receptors against which they were raised, besides being valuable probes for antigen identification. Antibodies may act as agonists, thus mimicking the natural ligands and promoting useful biological responses—for example, stimulating the survival and proliferation of cells in injured tissues. Conversely, they may behave as antagonists, inhibiting MET-mediated uncontrolled excessive responses of tumor cells. In the latter scenario, antibodies against the ligand could represent valuable tools for hampering the ligand–receptor interaction.Herein we review the properties of monoclonal antibodies directed against the HGF/MET receptor couple and their possible applications ranging from basic research to therapy. A brief summary of the structures of the two partners, instrumental for elucidating their interaction with the mAbs, is also presented.N-terminal hairpin segment followed by four disulphide-bond-stabilized kringle domains, while the β chain has the structure of a serine protease, but, due to the substitution of three amino acids, is devoid of enzymatic activity. HGF is secreted as an inactive single-chain precursor, which can be stored in tissues through high affinity binding to proteoglycans. In response to tissue injury, pro-HGF is then activated through proteolytic cleavage, to induce a local and transient burst of active HGF that promotes tissue regeneration [HGF is a multi-domain heterodimeric protein, consisting of two α and β subunits linked by a disulphide bond . The α cneration .MET receptor is a single-pass transmembrane heterodimeric tyrosine kinase glycoprotein, composed of two polypeptide subunits linked by disulphide bonds and consisting of different structural and functional domains . The extThe interaction between MET and its ligand HGF has not been fully elucidated. It appears to be quite complicated and to involve different binding sites on both molecules. The crystal structure of the HGF β-chain, in complex with the SEMA–PSI domain of MET ectodomain (ECD) , unveilei.e., dimerization-induced transphosphorylation of the receptor, is a requirement for some MET-mediated biological responses, such as cell proliferation [Experiments performed with mAbs clearly showed that receptor activation requires its dimerization, since it is strictly dependent on antibody bivalence. Indeed, monovalent Fab could not induce receptor transphosphorylation, which was recovered upon the addition of a secondary bivalent antibody . This exferation . Similarferation .i.e., phosphorylation on Y1230, Y1234, and Y1235, two other tyrosines (Y1349 and Y1356) embedded within a degenerate consensus sequence are phosphorylated and act as a double docking site for recruitment of both transducers and adaptors. This leads to the activation of multiple intracellular signaling pathways, the most important of which are the Ras→MAPK ERK1/2 and the PI 3 kinase→Akt pathways [After receptor activation, pathways ,23,36 (Apathways ).C-terminal 19 amino acids coupled to a carrier protein [C-terminal sequence, as well as antibodies against differentially phosphorylated forms of the MET protein [Depending on the desired antibody specificity, immunization was performed with different strategies. While mAbs targeting MET ectodomain were produced upon immunization with cells over-expressing the receptor ,51, or w protein ,54. Pept protein . Most of protein . Recombi protein  and, mor protein  have beewww.vai.org/met.Since by definition monoclonal antibodies are reagents of high specificity and affinity, from the beginning they have been used as probes to analyze the expression of MET on tumors and normal tissues ,53. BrieC-terminal peptide, contributed to identify C-terminally truncated receptor isoforms, as well as to elucidate their origin and biosynthetic pathways. Indeed, together with the full size 190 kDa MET protein, these antibodies immunoprecipitated two additional MET proteins of 140 and 130 kDa [MET), which is associated to the plasma membrane through its β chain, consists of a 50 kDa α chain and an 85 kDa β chain, which is truncated in its intracellular domain. The second protein (p130MET) is a soluble receptor isoform, which is released in the culture supernatant and consists of a 50 kDa α chain linked to a 75 kDa fragment of the β chain. Both truncated forms lack the tyrosine kinase domain, are basally produced from post-translational proteolysis [Historically, the first mAbs directed against the extracellular domain of MET, in combination with those against the intracellular  130 kDa . The firteolysis ,65, and teolysis ,67, can teolysis ,68,69. Iteolysis ,71. ThisE-cadherin and selectively exposed at the basolateral plasma membrane domain, where it is delivered directly from the Golgi apparatus during its synthesis [The antibodies against the MET ectodomain were also useful in elucidating the localization of the receptor in polarized epithelia. MET was found to be concentrated around the cell–cell contact zone, with a distribution pattern overlapping that of the cell adhesion molecule ynthesis . Indeed,89Zr can be used for imaging of MET-expressing tumors [In the era of targeted therapy, the eligibility of patients for a specific treatment depends on the presence of a precise genetic lesion and a molecular diagnosis is mandatory. In this context, MET antibodies may represent valuable diagnostic tools for immunohistochemistry and for use with non-invasive technologies such as PET and SPECT-Scan. Interestingly, the DN-30 anti-MET antibody (see next paragraph) labeled with the positron-emitting isotope g tumors .Many reports from the literature show that mAbs directed against the ectodomain of tyrosine kinase receptors can activate the receptor and trigger biological responses ,74,75,76In the case of MET, antibodies directed against the ectodomain allowed for dissection of the different biological responses and the correlated transduction pathways.in vivo angiogenesis [L. monocytogenes Internal B protein, which activates the MET receptor and promotes the bacterial invasion of the host cells, as identified by cross-inhibition experiments [Two antibodies (DO-24 and DN-31 ) that beogenesis ,80. Two ogenesis ,81,82. Aogenesis . Only thogenesis . By bindogenesis . In thiseriments  and co-ceriments .The DN-30 mAb is a partial MET agonist, but also behaves as an antagonist, and has been further developed as a monovalent antibody for anti-cancer therapy (see Antagonist MET mAbs section). The different contrasting activities of the bivalent form may be linked to the amount of mAbs used in the different experimental settings; indeed, the agonistic activity is generally more pronounced at low doses, and disappears at higher doses .The agonist mAbs were able to protect cardiomyoblasts from apoptosis induced by oxidative stress or by hypoxia induced by cobalt chloride treatment ,82. TheyThe development of antagonist antibodies directed against MET has been hindered by the intrinsic bivalent nature of antibodies. In fact, MET activation is a consequence of the approach of two or more receptors that transphosphorylate each other and start the signal transduction cascade. This early event is prompted mainly by the interaction of MET with its ligand HGF or by the physical proximity of receptors at the cell membrane due to MET over-expression. Binding of a bivalent antibody to the extracellular region of MET may induce receptor homodimerization and subsequent downstream activation, thus generating an agonistic rather than an antagonistic outcome. This problem may be circumvented by engineering monovalent antibodies devoid of ligand-mimetic properties.in vivo, thus providing onartuzumab with good pharmacokinetic properties. Onartuzumab acts by competing with HGF, in particular with the NK1 portion of the HGF α-chain, for binding to MET. Upon crystallization of a ternary complex composed of the antibody in the Fab format, the SEMA–PSI domain of MET, and the β-chain of HGF, the exact amino acid residues of MET involved in onartuzumab binding have been identified. They are located within blades 4–6 of SEMA β-propeller and overlap with the secondary binding site of the Listeria monocytogenes protein Internalin B. This antibody inhibited tumor growth in HGF-dependent preclinical models of glioblastomas [It is not the case that the most advanced MET antibody in clinical evaluation, onartuzumab , is the lastomas , and sholastomas . Phase Ilastomas . Howeverlastomas . Two addin vitro proliferation assays. In preclinical models of MET-driven human gastric and lung carcinoma [in vivo activity [Fab gene delivery allows continuous and sustained production of the therapeutic molecule by the host, and gave encouraging results in two preclinical models of MET-driven cancers [A similar strategy was pursued in the case of the bivalent antibody DN-30 , which aarcinoma ,95, as warcinoma , DN-30 Factivity . Recentl cancers ,95. Gene2 and CH3). The VHH domain corresponds to the structural and functional domain of the Fab fragment of conventional antibodies. Nanobodies  are isolated recombinant VHHs that retain the full antigen-binding capacity of the original HCAb. An anti-MET nanobody was generated by combining two different building blocks, one targeting MET and the other binding human serum albumin, for half-life extension. It binds with high affinity to MET and displays in vitro inhibitory activity on human myeloma cells harboring a MET-HGF autocrine loop [Humanized anti-MET nanobodies represent another approach to the generation of monovalent antibody-derived molecules able to bypass the risk of inducing an agonistic response. Nanobodies derive from heavy chain antibodies, discovered in Camelidae in the early 1990s. The Camelidae humoral immune response is peculiar: In the serum of these animals conventional antibodies coexist with the so-called heavy chain antibodies (HCAbs), functional heavy chain homodimers that do not associate with a light chain and lack the first heavy chain domain . Therefoine loop .E. coli and therefore aglycosylated [In recent years, a number of bivalent MET-targeting antibodies have been developed, and some of them are currently under clinical investigation. Many efforts have been made to identify full-length antibodies combining strong inhibitory properties with a negligible agonistic activity. In fact, the importance of antibody effector functions has progressively emerged, and antibody-dependent cytotoxicity (ADCC) especially has been demonstrated to play a major role in antibody efficacy . Cytotoxosylated .R13 and R28  are two A panel of antibodies (designated LMH) was generated by mice immunization with isolated MET SEMA domain or MET-expressing cells . Their mIn vitro, it displayed inhibitory properties in ligand-dependent biochemical and biological assays. In vivo, it delayed the growth of U87-MG human glioblastoma cells, which express both MET and HGF. Surprisingly, CE-355621 also exhibited robust inhibitory activity against GTL16 tumors, in which MET is constitutively phosphorylated due to gene amplification and receptor over-expression. Further investigations are required to elucidate the mechanism of action of this antibody in the case of HGF-independent MET activation.CE-355621 derives from a panel of human monoclonal antibodies generated by immunizing XenoMouse transgenic mice with a fusion protein between the extracellular portion of MET and the Fc domain of human IgG (MET ECD-Fc), or with NIH-3T3 cells over-expressing human MET . These aSAIT301 is a humanized antibody that promotes MET degradation by the LRIG-mediated lysosomal pathway, which does not require receptor activation for its function . SAIT301A series of 21 antibodies—termed Specifically Engaging Extracellular MET (seeMET)—were generated by mice immunization with a purified MET α-chain . They biin vitro. In MET-dependent preclinical models, it inhibited the growth of both HGF-activated and constitutively phosphorylated tumor cell lines. In a Phase I clinical trial currently ongoing in subjects with advanced solid tumors, it is well tolerated and has demonstrated promising anti-tumor activity in patients carrying the MET gene amplification [H224G11/ABT700 and LY2875358 are the first two bivalent anti-MET antibodies that entered clinical testing. H224G11/ABT700 is a humanized IgG1 antibody endowed with a fully antagonist activity , which rfication .in vivo models of both HGF-dependent and HGF-independent MET activation, including a MET-amplified lung cancer xenopatient. LY2875358 has completed a Phase I dose escalation study in patients with advanced solid tumors [The humanized IgG4 antibody LY2875358 competes with HGF for binding to MET, and induces receptor internalization and degradation . It recod tumors  and is uRecently, another panel of bivalent antibodies binding MET with high affinity has been characterized . These aInhibition of the HGF/MET pathway may be also achieved by HGF-targeting antibodies, which sequester the ligand thereby preventing receptor activation. This approach, however, presents some bias: first of all, HGF is stored as an inactive precursor in the extracellular matrix of tissues, which represents an almost unlimited source of this factor. Furthermore, MET activation in cancer is often ligand-independent, deriving from genetic lesions as activating mutations, gene amplification, or post-transcriptional modifications. However, HGF derived from the tumor microenvironment has recently been shown to protect MET-amplified cells, otherwise sensitive to MET inhibitors, suggesting a role for the ligand in the resistance to anti-MET therapy, and providing the basis for the use of HGF-neutralizing drugs . FinallyA number of anti-HGF antibodies have been generated. Among them, rilotumumab  and ficlin vitro and in vivo, but, unexpectedly, to also disrupt HER–MET crosstalk [The finding that MET can be activated through extensive cross-talk with other ligand/receptor couples ,32,33,34rosstalk .in vivo is critical and must be carefully evaluated. On the other hand, their relatively short half-life in vivo, as well as the possibility that they can be rapidly and extensively consumed in vivo both by tumor and host cells [In the context of cancer therapeutic applications, the same general disadvantages reported for other mAbs are present also in the case of anti-MET mAbs. Because of intrinsic bivalent Ab structure and the possibility of a mAb exerting both agonist—although only partial—and antagonist activity depending on the amount used, the amount administered st cells  through in vivo” [Nanomedicine is a new field of medicine that exploits the properties of nanosized materials. In particular, nanoparticles have revitalized the ancient concept advanced by Paul Erlich of the “magic bullet” that can specifically target tumor cells. Indeed, because of their nanosize and thus their high surface/volume ratio and high surface bioreactivity, nanoparticles can be viewed as efficient multifunctional platform carriers for drug delivery and imaging probes and, if functionalized with probes for tumor markers, can be directed to the desired target ,117,118.in vivo” . This apThe HGF/MET system can act as a double-edged sword, promoting both beneficial biological responses, as in the case of organ development during embryogenesis and tissue homeostasis in adults, and detrimental effects, as in the case of the uncontrolled cell proliferation of tumors. Monoclonal antibodies, which are extremely robust, specific, and versatile reagents, have achieved considerable success in cancer therapy over the past 15 years. MET-targeting antibodies endowed with antagonistic activities are currently under clinical evaluation in a variety of tumors, and appear to be promising tools for therapy. One of the limits of receptor tyrosine kinase (RTK)-targeted monotherapies, whether for antibodies or small molecules, is that only patients carrying a specific genetic lesion are suitable for the treatment, and even in the presence of the appropriate target not all patients respond to the therapy (primary resistance); furthermore, responding patients invariably develop resistance following treatment (secondary resistance). Combined targeting of different receptors, for example MET and EGF, the use of multitargeting inhibitors, or the association of targeted therapy and chemotherapy are promising strategies that are currently under clinical evaluation. Bispecific antibodies, simultaneously blocking multiple targets, represent a new and interesting tool .Conversely, anti-MET antibodies inducing only some of the pleiotropic effects mediated by the receptor make feasible their use as agonists in the appropriate contexts, as in liver and kidney regeneration or myocardial protection. Their ability to induce partial MET activation, thereby evading HGF-induced undesirable activities, together with their enhanced stability, provide partial agonistic MET antibodies with great potential for application in regenerative medicine; more effort should be put into this relatively new field.


This study examined the relative efficacy of social support seeking (SSS) and self-efficacy building (SEB) in the management of emotional well-being of caregivers of people suffering from HIV/AIDS. It was based at the United States President's Emergency Plan for AIDS Relief (PEPFAR) center in the University College Hospital, Ibadan, Oyo state, being the first and the largest teaching hospital in Nigeria. A 3 × 2 factorial design consisting of treatment and a control group was used. The columns have two levels of gender being male and female caregivers. One-hundred and sixty-five (165) caregivers who were taking care of people that are suffering from HIV/AIDS were purposively selected and randomly assigned to the treatment groups and control. The treatment was carried out for a period of eight weeks. Two null hypotheses were tested, both at .05 levels of significance. Data were collected with the use of standardized intruments rating scale; social support scale, general self-efficacy scale and emotional well-being scale. ANCOVA was used to establish significant treatment effects with the pretest as covariate. Even though SSS and SEB were both found to be effective in enhancing the emotional well-being of informal caregivers in this study when compared to the controls, SSS was significantly more effective than SEB in achieving this goal. Since the HIV/AIDS patients cannot be adequately cared for in the hospital settings due to severe shortages of material, personnel and time, serious efforts should be made by the three levels of the health care system viz: the primary, secondary and tertiary health care systems, to encourage the employment of the psychological management of caregivers of people suffering from HIV/AIDS. Also, the psychologists, clinical psychologists and the significant others should be encouraged to employ this psychological management in the care of HIV/AIDS informal caregivers. The past two decades have seen both the emergence of AIDS as a new life-threatening disease and its conversion from a rapidly fatal illness into a manageable chronic disease. HIV/AIDS has been a great challenge to the country since the first case of AIDS was identified in Nigeria in 1986. The HIV/AIDS is a life-threatening infectious disease, and major advances in highly active antiretroviral therapy (HAART) have converted the disease into a manageable chronic disease, leading to declines in rates of opportunistic infections and deaths. However, even in this period of highly active therapy, AIDS remains dreadful epidemic and an important cause of morbidity and mortality in many young adult populations in Africa.The dire situation in many homes and communities in Nigeria is a serious challenge to the work of HIV/AIDS caregiving. Being a HIV/AIDS patient can be a highly emotional experience, thus a system of support is crucial for these individuals, to strengthen their coping strategies when dealing with this disease. The support is often provided not only by professionals, but mostly by the individuals who provide assistance to them at home, regarded as the informal caregivers. They are family and friends of people living with HIV/AIDS (PLWHA), who give individuals living with HIV/AIDS emotional, spiritual and physical care in dealing with the effects of HIV/AIDS on their daily lives. The informal caregivers include significant others like parents, children, relatives, spouse/partners and friends who provide in-home care, usually on an unpaid basis. These informal caregivers share the same constraints, needs and challenges that their relatives living with HIV/AIDS do, such as grief, fear of impending death, stress, burnout and social problems such as poverty, lack of food and proper housing, ill health, inability to access health care treatment for relatives and above all, lack of training and information about the disease, care, prolongation and illness progression.Unfortunately, only a limited number of resources are designed specifically to help the informal caregivers deal with the effects of HIV/AIDS in Nigeria. Recent reforms in health care systems have made individuals with long-term complex health problems such as HIV/AIDS, to be cared for at home by family members  and 69.2% (1.8 million) occurred in Sub-Saharan Africa. A large proportion of these cases occurred in Nigeria. With the current National prevalence of 4.1%, the number of people infected is estimated at about 3.1 million. This means that Nigeria still has the second largest number of PLWHA in Sub-Saharan and the highest in West African sub-region. Currently, about 1.5 million people including 212,720 children are still in need of AIDS treatment. Around 636,000 people were estimated to require Antiretroviral Therapy (ART) in Nigeria .The role of the informal caregiver is thus very significant for PLWHA. Informal caregivers perform a variety of roles that help people with AIDS to adhere to treatment regimens, avoid unnecessary hospital admissions, reduce the need for formal caregivers, remain at home longer and maintain a good quality of life. Traditionally, family members have served as the primary caregivers for seriously ill individuals. Because HIV care involves more diverse social networks, many HIV-positive individuals have redefined family boundaries to include lovers, friends and other “chosen kin”. Thus, a chronic illness such as HIV/AIDS affects not only the lives of those suffering from the disease, but also those of family members who care for them.et al. The caregiving exerts increased AIDS financial, physical and emotional responsibility on family members who care for their relatives with HIV/AIDS  on the caregivers' well-being  and self-efficacy building (SEB) strategies are effective in enhancing emotional well-being of HIV/AIDS caregivers. Also, to find out which of the two treatment strategies is more effective in enhancing emotional well-being of the caregivers and finally to establish cause–effect relationship between SSS and SEB treatments.This was an experimental study, exploring a 3 × 2 factorial design. It involved two treatment groups and control or no treatment group. The row consists of SSS treatment, SEB treatment and the control. While the column consists of gender labeled as male and female.The population consists of informal or family caregivers of PLWHA at the President's Emergency Plan for AIDS Relief (PEPFAR) center, University College Hospital (UCH), Ibadan, Oyo state, Nigeria.Sample size of the study consists of one-hundred and sixty-five (165) caregivers, 56 males and 109 females who are taking care of the HIV/AIDS patients with the diagnosis being confirmed by physicians using formula to determine the difference between two proportions, with the expected power of 90%, using a study where proportion of clients in intervention and control groups based on their responses to the instruments administered were (58%) and (32%), respectively.Purposive sampling and randomization methods were used to select participants and assigned participants in groups. The purposive sampling technique was used because selection of sample from the population of the study was done according to the purpose of the study. Random sampling was used to select final participants. This was done by making sure that all the participants were given equal chance of participation. The researcher used a table random sampling where participants were allowed to pick yes or no wrapped in papers.The study was carried out in 2009 at the PEPFAR center, UCH, Ibadan, the first and the largest federal teaching hospital in Nigeria.Data collection for the study was carried out using three instruments which consisted of four sections. Section A consisted of several items tapping respondents’ socio-demographic variables, such as age, sex, family, socio-economic status, occupation, etc.Social support scale (SSS) was measured using a multidimensional scale of perceived social support development by Zimet, Dahlem, Zimet, and Farley . It was It is a 12-item format scale which is scored on five points ranging from 1 (strongly disagree) to 5 (strongly agree). The items on the scale were loaded into factor groups relating to the source of the social support namely family (fam), friends (fri) or significant other (so). Higher scores indicated high level of satisfaction with social support while low scores indicated low level of social support.This scale was developed by Scholz, Gutiérrez Doña, Sud, and Schwarzer . It was et al. Emotional well-being was measured here using the General Health Questionnaire (GHQ). It is a 28-item scale developed by Goldberg, Gater, Sartorius, Ustun, Puccinelli, Gureje The scale is designed to measure individuals’ well-being in respect of their emotional disturbances. The scale has four subscales which include somatic symptoms 7 items, social depth 7 items, anxiety and insomnia 7 items and social depression 7 items. The authors reported Cronbach Coefficient alpha between 0.82 and 0.86. Jones, Rona, Hooper, and Wesseley  and IdemThe caregivers 165 in number were purposefully selected and randomly assigned to treatment groups and control thus SSS – 55; SEB – 55 and control group – 55. The participants were exposed to treatment for a period of eight (8) weeks, while the control was met weekly without any treatment.There will be no significant treatment effects in the emotional well-being of the participants in the experimental groups (SSS and SEB Treatment Strategies) and control group.There will be no significant difference in the emotional well-being of the participants in the experimental group (SSS and SEB Treatment Strategies).Ethical clearance was obtained from the University of Ibadan/UCH ethics committee and ethical considerations were observed throughout the study.ANCOVA statistical tool was used to analyze the data collected. This was used to establish the significant treatment effects with the pretest as covariate.The findings of this study with particular reference to the hypotheses are discussed.The first hypothesis states that there will be no significant treatment effects in the emotional well-being of the participants in the experimental groups (SSS and SEB Treatment Strategies) and control group.Y-means of the treatment groups . The results of the findings show that the adjusted Y-means scores of the two treatments were better than the control group meaning that there was effectiveness of the two treatments over the control.F = 20.79; P < .05. This again indicates that the two treatments were effective in enhancing emotional well-being of the participants.Hypothesis Two: The hypothesis states that there will be no significant difference in the emotional well-being of the participants in the experimental group (SSS and SEB Treatment Strategies).Y-means of the treatment groups. The SSS group was superior to the SEB group in enhancing emotional well-being of the participants in the study.F = 10.03, P < .05. This indicates that the two treatments were effective in enhancing emotional well-being of the participants. However, the result showed SSST mean score (X = 59.29) and SSBT (X = 58.20), indicating the superiority of SSS treatment over SEB treatment in improving the emotional well-being of informal HIV/AIDS caregivers.The result from et al. (et al. (This study aimed at finding out the relative efficacy of SSS and SEB in the management of emotional well-being of caregivers of people suffering from HIV/AIDS in Ibadan, Oyo state, Nigeria, with the aim of whether the independent variables can be used to enhance emotional well-being of caregivers of PLWHA and which of the strategies is more effective. The result of the findings revealed that the treatment effects were very effective and superior to the control group in enhancing emotional well-being of the participants. This finding corroborates the study of Spiegel, Butler, Gieses-Davis, Koopman, Miller, DiMiceli, et al. , who fou (et al.  found a  (et al.  found th (et al. , Rice (1 (et al.  and Vohs (et al.  study whIt was further observed that there were significant treatment effects of these two treatment groups when compared with each other and social support treatment strategy appeared as more effective than SEB strategy in enhancing emotional well-being of the participants. These findings corroborate Stajduhar and Davies  in theirResearch on self-efficacy has focused on the individual's capacity to monitor and modify behavior, cognition and affect in order to achieve a goal (Efklides, Niemivirta & Yamauchi The study has found that social support and self-efficacy strategies were very effective in enhancing emotional well-being of the participants in the study. It is believed that these two techniques will serve as key processes for achieving patient-focused, family-centered care as well as patients' outcomes care based on the social support and SEB training that had been given to the participants.Based on the findings of this study, it was recommended that strong link should be created between the different organizations in care and support of PLWHAS in communities and taken care of. Counseling should be extended to informal caregivers especially with regard to their emotional and psychological needs. Finally labor organizations and parastatals should implement work place support groups as a way to mitigate the impact of informal caregiving on workers. Thus, counseling, linkages and information services can be employed and sponsored in work place for informal caregiver support groups.The results reveal the appropriate psychological techniques that can be used by Nigerian clinical psychologists and other members of the health care team as an adjunct to the management of emotional well-being of the caregivers. In addition, the research has empirically demonstrated how the therapeutic techniques could be effectively used in the management of caregivers' emotional well-being. The mastery of the techniques by the caregivers/participants who participated in this study enabled them to be in control of their peculiar circumstances.


Medical tourism suffers from the lack of a consensus regarding the involved categories. This study aimed to address this gap from the academic disciplines and publications perspective.Totally 1954 citations were identified through a formula of keyword search of SCOPUS. In order to classify the various subject areas, we followed the international standard classification of education (ISCED) developed by UNESCO. Moreover, the trends of publications were identified based on their popularity between 2000 and 2017.The category with the most interests on publication about medical tourism was ‘health and welfare’, followed by ‘social science’. Even though various disciplines were involved in the medical tourism, it seems that a downward trend has been experienced since 2015.The identified key trends of medical tourism publications will benefit researchers exploring the categories of medical tourism or health travel. The results contribute to advance the state of knowledge from the academic perspective. Medical tourism emerged as a new type of healthcare mobility , 2 and sThis barrier not only does refer to the definition, but also the associated industry and service sector are suffering to clarify the involved categories. Those companies active in medical tourism are ‘integrate into the wider tourism industry’ . Many coIn order to address this shortage, a constructive attempt would be to explore the academic disciplines and program that have been included in the publications of medical tourism and health travel. It would also imply on the background of those researchers that are interested in medical tourism and accordingly would lead to the backbone of this multidisciplinary service from the academician and publication perspective; moreover, it could potentially result in a more accurate definition of medical tourism which is based on the practical studies and the available factual information.In order to classify the comprehensive research of medical tourism, a well-established category was required. From the perspective of journalism and academic publications, there are various types of classification. The most widely accepted classification is the international standard classification of education (ISCED) a framework developed by United Nations International Family of Economic and Social (UNESCO) . This clAccordingly, this study aimed to investigate the backbone of academic publications on medical tourism in order to clarify the variation of the involved disciplines. The objectives were 1) to determine the disciplines of the most renowned publications, 2) to determine the boundaries and quantity of those categories that were interested in medical tourism publications, 3) to explore the popularity of medical tourism publications during a period of time, and finally, 4) to clarify the trend of medical tourism scholarly publications.This exploratory research was conducted focusing on several questions. A comprehensive search was accomplished on the secondary data (publications indexed in SCOPUS) to retrieve the relevant articles. Afterward, data were classified based on the ISCED category. The process of the data collection and analysis are explained in the following sections.We searched the most renowned and well established academic databases. The search strategy was designed based on each database in order to maximize sensitivity. The main keywords included: . Searching these keywords in Google scholar, 16,800 results were found, also SCOPUS and science direct showed 1,954 and 612 results respectively. The information was updated two months before the publication so that the latest data could be analyzed.Given that this study was not searching for the contents of publications, rather it aimed to find the quantity and the main trend of this international health service and international patient’s mobility, we only focused on the data indexed in SCOPUS. The reason to focus only on one database was to cover the main trend among the mostly referable publications, also to exclude the possibility of article duplication in several databases. Moreover, the classifications of subjects differ based on each database regulations. Hence we decided to focus on one database and to classify the data in the ISCED category. On the other hand, finding the research trend through meta-analysis was not possible due to the heterogeneity of the topic .The references used in this study were all published during a time period of 2000 and 2017. Thus, this does not imply that those publications before 2000 were not significant, rather in the initial search we found that the main publication in this arena has been mainly started since 2005.As noted earlier, all data were collected from the database of SCOPUS. Searching the abovementioned formula, 1954 documents were found. These articles were analyzed based on two perspectives of ‘academic discipline’ and year of publication.The SCOPUS classify the documents from the perspective of ‘subject area’ which is designed based on the indexed keywords of each publication. Totally 27 ‘subject areas’ were presented for that formula of keywords we searched. In order to find the trend in an internationally accepted category, we attempted to reclassify those 27 categories (subject areas) based on the ISCED. This category which is developed by UNESCO seems to be the most comprehensive well-established framework for ‘analyzing cross-nationally comparable statistics on education’ . We applTotally, 1954 citations were searched; all were published between 2000 and 2017 and indexed in SCOPUS. The quantities of publications and the classification are listed in The category of ‘health and welfare’ has the highest amount of publications by 1461 cited articles. It was followed by the category of ‘social science’ with 657 publications. Third in terms of publication were those related to ‘business, administration and law’ counted for 307 publications; afterward, the category of ‘natural sciences and statistics’ with 253 publications and ‘art and humanities’ with 119, entitled as the fourth and the fifth most involved categories. The three categories with the fewest interests in publications, meanwhile, were ‘engineering and construction’, ‘information technologies’ and ‘agriculture’ with the rates of 98, 57 and 18, respectively.The trends of publications have been started since 2005 by the researchers with interest in the category of health and welfare; however, there are two critical periods of time for the other categories. It seems that 2008 and 2009 were the starting points for the researchers coming from different other disciplines to conduct their research regarding medical tourism. The second critical time period was 2015, the peak time for medical tourism publications among several categories, though those interests were followed by sharp downward trends. This pattern is true for almost all categories.Following the trends of all 10 ISCED  of research. We could infer from these figures that researchers from various disciplines are interested to conduct their research in the subject of medical tourism.It should be noted that the associated publications in SCOPUS could not cover all the available information, though; the results seem to be beneficial enough for being generalized and helpful to address a small part of available complexity and ambiguities. Furthermore, since we followed the classification of SCOPUS and ISCED, the results would be comparable with the further studies on other databases and other classifications.The wide ranges of the involved academic category in medical tourism publications were classified and the trends of those interests were presented. It could also imply on the academic backbone of this arena.Ethical issues  have been completely observed by the authors.