The petrochemical industry is a major source of hazardous and toxic air pollutants that are recognised to have mutagenic and carcinogenic properties. A wealth of occupational epidemiology literature exists around the petrochemical industry, with adverse haematological effects identified in employees exposed to ‘low’ concentrations of aromatic hydrocarbons . Releases from the petrochemical industry are also thought to increase the risk of cancer incidence in fenceline communities. However, this emerging and at times inconclusive evidence base remains fragmented. The present study’s aim was to conduct a systematic review and meta-analysis of epidemiological studies investigating the association between incidences of haematological malignancy and residential exposure to the petrochemical industry.Epidemiological studies reporting the risk of haematological malignancies  were included where the following criteria were met: (i) Cancer incidence is diagnosed by a medical professional and coded in accordance to the International Classification of Diseases; (ii) A clear definition of fenceline communities is provided, indicating the proximity between exposed residents and petrochemical activities; and (iii) Exposure is representative of normal operating conditions, not emergency events. Two investigators independently extracted information on study characteristics and outcomes in accordance with PRISMA and MOOSE guidelines. Relative risks and their 95% confidence intervals were pooled across studies for the four categories of haematological malignancy, using a random effects meta-analysis.The systematic review identified 16 unique studies, which collectively record the incidence of haematological malignancies across 187,585 residents living close to a petrochemical operation. Residents from fenceline communities, less than 5 km from a petrochemical facility , had a 30% higher risk of developing Leukaemia than residents from communities with no petrochemical activity. Meanwhile, the association between exposure and rarer forms of haematological malignancy remains uncertain, with further research required.The risk of developing Leukaemia appears higher in individuals living near a petrochemical facility. This highlights the need for further policy to regulate the release of carcinogens by industry. Haematological malignancies are cancers affecting the blood, bone marrow, lymph, and lymphatic system. The International Agency for Research on Cancer (IARC) classifies haematological malignancies into four broad categories: Leukaemia, Hodgkin Lymphoma, Non-Hodgkin Lymphoma and Multiple Myeloma , 2. In lThe petrochemical industry acts as a major source of hazardous and toxic air pollution and is associated with the release of a range of known carcinogens, such as volatile organic compounds, BTEX , polycyclic aromatic hydrocarbons, polychlorinated biphenyls and polyvinyl chloride , 7. The A wealth of occupational studies have identified adverse haematological effects in employees exposed to toxicants in the petrochemical industry . NotablyWhile evidence on the elevated occupational risk of developing haematological malignancies in the petrochemical industry is largely conclusive, toxic and hazardous releases from the industry are also understood to increase the risk of cancer incidence in fenceline communities. However, the evidence base documenting the blood cancer risks for populations living in close proximity to petrochemical operations remains inconclusive and disjointed. There is a need to enhance understanding of the specific health impacts of the petrochemical industry for fenceline communities, as an evidence base for environmental (in)justices.To our knowledge, there has been no meta-analysis thus far on the incidence of haematological malignancies in fenceline communities living near petrochemical sites. To fill this gap, we conduct a meta-analysis of cohort and case-control studies that have examined the incidences of haematological malignancies in residential populations close to petrochemical sites. For this we build upon Lin et al.’s meta-analyses of lung cancer mortality  and inciCRD42019118567), to avoid the duplication of research and for transparency purposes by providing evidence of a priori analysis intentions. This procedure minimises the introduction of bias by hypothesising after the results are known, otherwise known as ‘HARRKing’, whereby findings are omitted or accommodated to achieve a more desirable outcome  programming language, using the ‘metafor’ package version 2.1 .Activists have long argued that the petrochemical industry has severely harmed the health of people living in Louisiana; however, first-hand quantitative evidence has been notoriously difficult to gather: Research has reportedly been terminated over safety fears, and local cancer registries have been spatiotemporally censored at low resolution units, debatably over disclosure concerns or to conveniently mask trends within the data , 63.Using the knowledge gained from these meta-analysis models, we intend to conservatively estimate the impact of petrochemical activity on haematological malignancy incidence in Louisiana from 2011 to 15, based on the following approach.While the ‘Upstream’ component of the petrochemical industry is clearly defined (i.e. refineries), difficulties exist in the identification of ‘Downstream’ activities, and links start to blur as petroleum feedstock is gradually restructured into ever more complex chemical components. Still, most forms of petrochemical activity may be traced by the release of volatile aromatic hydrocarbons, in the form of benzene, toluene, ethylbenzene, and xylene compounds (BTEX).We assumed that ‘Upstream’ activities are the most polluting aspect of the industry, as they process and break down the largest volumes of petrochemical feedstock. Table n = 29). The selected facilities are considered as ‘highly’ polluting, even by historic levels. Standard industrial classification (SIC) codes identified 8 refineries, 1 midstream storage facility, and 10 downstream manufacturers of commercially marketable products in the form of organic chemicals, plastics and fertilisers. Fifteen of these ‘highly’ polluting petrochemical facilities were located on the Mississippi (79%). Ten facilities were omitted from the analysis for not processing hydrocarbons, which highlights the additional risk posed by other industrial activity, particularly from the fabrication of metals at shipyards.We first identified all industries operating in Louisiana between 2011 and 2015, which released emissions of a BTEX compound above or equal to the median emission level of refineries in 1987  was then used to identify ‘highly’ polluting petrochemical facilities, and a 30x30m population grid was used to estimate the size of their fenceline communities .For each individual parish, a ‘Population Attributable Fraction’ (PAF) estimated the proportion of haematological malignancy incidence, attributable to residential exposure from the petrochemical industry :\documePpop represents the proportion of a parish residing within 5 km of a petrochemical facility (i.e. the proportion of exposed subjects), and RR is the pooled relative risk of a particular outcome occurring in the exposed population, as estimated by the meta-analysis models.Where The systematic review identified 16 unique studies, which collectively record the incidence of haematological malignancies across 187,585 residents living close to a petrochemical operation . In terms of petrochemical activity, 9 of the population groups lived near to “upstream” refinery operations, 4 lived near to “downstream” facilities producing commercially marketable chemical products, and 8 lived alongside both forms of petrochemical activity. Fenceline communities were typically defined as living within 5 km of a petrochemical facility, although a few authors used an exposure threshold of up to 8 km in their analysis , 56, 67.The quality of the existing literature was assessed via the Newcastle-Ottawa scale, which evaluates the risk of bias introduced by the selection of participants, their comparability to reference populations, and differing definitions of exposure (see Tables 2 < 1%). Based on this evidence, the subsequent analysis focused on communities within 5 km of a petrochemical facility.Figure 2 = 52.2%), which must be accounted for, in order to test the robustness of these findings.A pooled RR of 1.30 (95% CI = 1.09 to 1.55) indicates that leukaemia incidence is higher in fenceline communities no more than 5 km away from petrochemical activity. Beale et al’s  gender-bM), where p > 0.05 rejects the null hypothesis of no relationship between the effect size and moderator variable(s). Any remaining sources of heterogeneity found in the model’s residuals are considered of negligible influence, if the I2 test returns a value below 25%, and or Cochran’s Q rejects its null hypothesis .A series of meta-regressions were conducted to identify and control for potential causes of heterogeneity in the risk of leukaemia incidence for fenceline communities . The petrochemical industry also appears to pose a common risk, regardless of any differences in operational practices at either a continental  or national  level of analysis. The presence of confounding caused by revisions to the classification schemes used to diagnose blood cancers was then tested for, the impact of which appears to be negligible .The meta-regressions identified no differences in risk from residential exposure to a specific sector of the petrochemical industry, be that from an upstream refinery or downstream manufacturer of petroleum-based goods (Q2 < 1%). The participant selection processes were critiqued based on the format of underlying data (i.e. record linkage or self-reports), its validity, and the representativeness of sampling procedures.Heterogeneity between the individual study effects appears to be linked to aspects of study quality, measured by the three underlying themes of the Newcastle-Ottawa scale. Virtually all traces of heterogeneity were removed when controlling for differences in quality, based on the “Participant Selection” process of each study , and no publication bias exists amongst the identified studies .The pooled RR of leukaemia incidence in fenceline communities increased to 1.58 (95% CI = 1.32 to 1.90), after controlling for participant selection. The meta-regression outputs confirm that any variation in study design is sufficiently accounted for (I2 < 1%), and surprisingly reported an increase in risk with time  or publication bias , and the highest rates of risk are still found in the most recent population studies. The RR of leukaemia incidence from petrochemical operations in 2011 is estimated at 1.88 (95% CI = 1.32 to 2.67), compared to 1.38 (95% CI = 1.02 to 1.87) in 1971. Although it is unlikely that an increasingly regulated industry will pose the greater risk, we can conclude that the potential risk of petrochemical operations certainly has not diminished over time..A final meta-regression was created, which controlled for quality (in terms of participant selection) and the initial reporting year of each study , Hodgkin’s Lymphoma (HL), and Multiple Myeloma (MM).2 < 1%, QEp-value = 0.89). The creation of a symmetrically distributed funnel plot , a somewhat asymmetric funnel plot and close rejection Egger’s test  may indicate publication bias.Figure 2 ≈ 41%). The variation in effect size appeared to be linked to study quality, as measured by the Newcastle-Ottawa scale overall score (I2 < 1%). The resulting revised model found no clear link between Multiple Myeloma and residential exposure to the petrochemical industry .Finally, a pooled RR estimate of Multiple Myeloma incidence in fenceline communities was constructed from gender-specific effects, reported by 3 different studies see Fig. . Whilst Louisiana is located within the southeastern United States, where the Mississippi River meets with the Gulf of Mexico. It is considered one of the most toxic states, annually discharging 7.2 t of hazardous waste per capita, and accounting for 12.5% of the country’s hazardous waste from only 6.5% of the nation’s chemical facilities , 78. Then = 82,554).Table It is estimated that the petrochemical industry is accountable for 58.7 (27.8 to 105.1) new cases of leukaemia in fenceline communities along this river corridor, over the 5-year period of 2011–15, when applying our meta-analysis risk ratio to parish level health data. Figure The systematic review and meta-analysis identified 16 unique studies which collectively record the incidence of haematological malignancies across 187,585 residents living in close proximity to petrochemical sites. Across varied geographical contexts and covering a period of analysis between 1960 and 2011, the review found that those living within 5 km of a petrochemical facility have a 30% higher risk of developing leukaemia than residents from communities with no petrochemical activity. The enhanced risk for fenceline communities applied to upstream, midstream and downstream petrochemical operations.The analysis indicated that heterogeneity between the 16 studies may be explained by differences in study quality, notably in relation to the participant selection process of the research. The meta-analysis also found temporal differences, with the most recent exposure studies reporting the highest rates of leukaemia risk in fenceline communities. Given the increasingly regulated nature of the petrochemical industry, this was an unexpected and surprising finding. It is plausible that the earliest studies investigated sites representative of the wider industry, with later research guided by a wealth of anecdotal evidence and primarily focusing on the most polluting operations.. Thus, we do not suggest that the risk of developing leukaemia in fenceline communities is becoming greater, but rather that the risk for residents living close to petrochemical sites persists.The incidences of Non-Hodgkin’s Lymphoma (NHL), Hodgkin’s Lymphoma (HL), and Multiple Myeloma (MM) in fenceline communities remain uncertain and further research is required to determine the risk of developing these blood cancers in fenceline communities of petrochemical sites.Building on the meta-analysis, we estimate the potential impact of the petrochemical industry on leukaemia incidence in Louisiana’s Mississippi Valley, between 2011 and 2015. Nineteen petrochemical facilities in the state of Louisiana, were currently found to release emissions of a BTEX compound above or equal to expected industry levels in 1987, fifteen of which are located close to the Mississippi. It is estimated that 188,075 residents from 12 parishes along Louisiana’s Mississippi Valley, known as ‘Cancer Alley’, live within 5 km of a ‘highly’ polluting petrochemical facility. The findings suggest that the petrochemical industry is accountable for 58.7 new cases of leukaemia in fenceline communities in ‘Cancer Alley’, between 2011 and 2015. This estimate is thought to be conservative, as we only considered the impact from 15 out of 54 identifiable petrochemical facilities from these 12 parishes (28%), based on the criteria of ‘high’ levels of BTEX emissions under normal operating conditions.The findings from this meta-analysis support existing occupational research on the incidence of haematological malignancies among workers in the petrochemical industry, which observed close associations between exposure to toxic pollutants and the development of blood cancers across the upstream, midstream and downstream sectors of the industry , 34, 35.The findings from this meta-analysis extend previous epidemiological research on associations between residential exposure to releases from petrochemical facilities and health risk. It adds to Lin et al’s , 8 meta-This is the first known meta-analysis of blood cancer risk in fenceline communities next to petrochemical industrial sites. The meta-analysis investigated the association between incidences of haematological malignancies and residential exposure to releases from the petrochemical industry. The analysis of incidence rates rather than mortality rates can reduce the bias caused by other factors which may affect blood cancer survival rates  , 80.The meta-analysis adopted a rigorous study selection process, including a comprehensive search of relevant academic databases and a strict application of criteria in selecting studies. All incident cases in the identified studies were diagnosed by a medical professional and coded in accordance to the International Classification of Diseases (ICD). Furthermore, studies were only included if they reported health outcomes under normal operating conditions (not emergency events), and if they provided a clear definition of fenceline communities, thus avoiding the limitations of Lin et al’s , 8 meta-However, given that the identified 16 studies are clustered in three geographical regions, there may exist concerns over generalisability in this meta-analysis. Exposure levels and health conditions may be affected by geographical differences in environmental law, housing regulations, and access to healthcare, yet we observed no unexplained discrepancies between the European and North American literature. Moreover, there are difficulties in assessing the health impacts of pollution from the petrochemical industry in one discrete time period, as these studies did. Blood cancers may develop years after exposure and the slow temporal dimensions of pollution may be a possible explanation for why the later studies indicated higher risk levels of leukaemia in fenceline communities. Additionally, the quality assessments carried out using the Newcastle-Ottawa scale are subjective and limited, in that we can never know the full extent of the studies’ quality and can only judge by the information provided by the investigators.Furthermore, other risk factors, notably socioeconomic status, were often not universally adjusted for by the selected studies, which may influence the findings . AlthougAll studies examined in this systematic review indirectly measured exposure to a petrochemical facility in terms of proximity, however, exposure can only be truly confirmed by direct measurements of air quality and biospecimens (i.e. a complete exposure pathway). Only two of our identified studies provided exposure measurements, which crudely summarised the areas of high and low exposure , 68, andThe meta-analysis provides evidence for a higher risk of leukaemia development in individuals living near a petrochemical facility, due to exposure to toxic and hazardous emissions. Meta-analysis findings such as these can act as evidence base for public health policy priorities, including the setting up of preventive strategies and standards, and the tightening of regulations on toxic and hazardous pollutants from the petrochemical industry. Our findings can also be used to assist legal cases of grassroots environmental movements whose research capacities may be limited or hindered by the power and influence of industry.Additional file 1.


The decisive etiology of oral squamous cell carcinoma (OSCC) is still ambiguous, but we recognize the contribution of genetic aberration and environmental agents due to OSCC initiation. In the current study, we elucidate the potential impact of EGFR gene polymorphisms on the risk of OSCC in Southeast Iran.Forty-eight OSCC patients along with 100 healthy volunteers were included. Three polymorphisms of the EGFR gene  were genotype by Tetra-ARMS PCR. Data were analyzed with a chi-square test, and p<0.05 was considered significant.In rs2227983, the frequency of AG and GG genotypes were 62.5%, 37.5% in cases and 42%, 57% in the control group  and also A allele frequency was 31.3% in the case and 22% in control . AG + AA genotype frequency was 62.5% and 43% in case and control, respectively . In rs2227984 and rs2293347, no statistical differences showed in the distribution of genotypes between the case and control group. Also the majority of the OSCC belonged to grade I (43.8%).The present investigation indicated that rs2227983 polymorphism might contribute to OSCC susceptibility in Iran's southeast population. Although, with the inconsistent interpretation mentioned due to the various geographical residencies and populations, more studies of significant populations are suggested to validate our findings. Head and neck neoplasm is the sixth most widespread epithelial cancer worldwide . Oral sqRTKs are operated as receptors for hormones, growth factors, cytokines and extracellular signaling molecules . Moreove) and epidermal growth factor (EGF)  . This reor (EGF) . EGFR ovor (EGF) . In addior (EGF) . Evidencor (EGF) . Furthermore, both the in-vitro and in vivo studies have displayed the potential impact of these proteins in cell transformation . IncreasMolecular epidemiologic studies in 2006 showed that EGFR gene variations might be related to alteration in cellular biological activities . NeverthStudy population: In this case-control study, forty-eight OSCC patients and 100 healthy subjects were studied. All of the OSCC patients were histologically confirmed by two maxillofacial pathologists that referred to the Dentistry Faculty of Zahedan University of Medical Sciences in 2017. All histopathological slides of OSCC samples were classified into three grades, including well-differentiated (grade I), moderately differentiated (grade II) and poorly differentiated (grade III) by maxillofacial pathologists .DNA isolation and polymorphisms genotyping: Genomic DNA was isolated from the paraffin-embedded tissue blocks of OSCC patients by standard extraction procure  were genotyped using tetra-ARMS PCR techniques. The primer sequences and product size have been summarized in The EGFR single nucleotide polymorphisms rs2227983(R497K), rs2227984 (T584T) and rs2293347 . The chi-square test was used to compare quantitative variables between the two groups. The odds ratios (ORs) and 95% confidence intervals (CIs) for overall OSCC were estimated, seeking the probable correlation between EGFR polymorphisms and OSCC susceptibility. A p-value < 0.05 was considered remarkable.In the current research, three single nucleotide polymorphisms assessed in the EGFR gene in 48 OSCC patients include 17 (35.42%) males, 31 (64.58%) females and 100 control individuals, 57 females and 43 males. The mean age of the case and control groups were 58±13 and 55±10 years, respectively. As shown in OSCC is a multifactorial disease represented in about 90% of oral cancer worldwide . Most st- In rs2227983, with a G→A substitution leading to an Arginine (Arg) →Lysine (Lys) change in codon 497. The results showed that the heterozygous AG variation was common in patients than the control individuals. Also, results indicated that the presence of A allele at rs2227983 polymorphic site (AG + AA) of the EGFR gene is related to OSCC susceptibility and this genotype is in association with OSCC predisposition. With regard the allelic distribution of G and A in rs2227983, the respective frequencies were not remarkably diverse from the ratios observed in the control healthy (68% vs 78% and 31 vs 22% respectively). In the USA population, the G and A allele frequencies were observed as 67% and 33 %, respectively, in Southern Asia, showed a similar frequency  . Moriai - In rs2293347, with an A→G substitution leading to an aspartate (ASP) change in codon 994 to the same amino acid in the coding region of exon 25. This synonymous SNP may not involve the biological activity of the protein itself . However-In rs2227984, with a T→A synonymous substitution leading to threonine (Thr) shift in codon 584 that means replacing a codon with another codon of the same amino acid . This stIn conclusion this study indicated that the EGFR G>A (rs2227983) polymorphism was the promising predictor factor in OSCC patients in the southeast population of Iran. However, our data can not yet definitely emphasize the role of EGFR gene variations. It seems that this receptor participates in essential signaling pathways of cell cycles and then may be used as a biomarker in response to chemotherapy. Although, with the inconsistent interpretation mentioned due to the various geographical residencies, different populations and ethical diversities, more studies in major populations are suggested to be performed to validate our findings.


Clients and therapists often have different perspectives on their therapeutic alliance (TA), affecting the process and outcome of therapy. The aim of the present meta-analysis was to assess the mean differences between clients’ and therapists’ estimations of TA among clients with severe disturbances, while focusing on two potential moderators: client diagnosis and alliance instrument.d standardized mean effect size.We conducted a systematic literature search of studies examining both client perspective and therapist perspective on TA in psychotherapy among people with schizophrenia spectrum disorders, personality disorders, and substance misuse disorders. We then analyzed the data using a random-effects meta-analytic model with Cohen’s k = 22, Cohen’s d = −.46, 95% confidence interval = .31–1.1) produced a significant Q-statistic (Q = 94.96) and indicated high heterogeneity, suggesting that moderator analyses were appropriate.Heterogeneity analyses (Our findings show that the type of TA instrument moderates the agreement on TA between client and therapist, but there was no indication of the client’s diagnosis moderating the effect. The agreement between client and therapist estimations seems to be dependent on the instrument that is used to assess TA. Specific setting-related instruments seem to result in higher agreement between clients’ and therapists’ estimations than do more general instruments that are applied to assess TA. Bordin’ ratings –7.d = 0.63) [The agreement between therapists’ and clients’ TA estimations plays an important role in determining both therapy process evaluations and therapy outcomes. Marmarosh and Kivlighan  found th = 0.63) . The aut = 0.63) . The curIn line with previous meta-analyses on the topic, we defined client-therapist agreement as the degree to which client and therapist estimations converge or diverge, represented by client-therapist mean difference scores of the TA . The curThe current work aimed to deepen the understanding of the role of specific diagnosis on the agreement on TA. However, whereas Tryon, Blackwell, and Hammel  categoriIn addition to the examination of diagnosis as a possible moderator, different scales conceptualize TA differently and emphasize slightly different aspects of the therapeutic relationship , suggestThe present meta-analysis explored agreement on TA between clients and their therapists among individuals with serious mental illness, focusing on two potential moderators: client diagnosis and the type of instrument that assesses TA.A systematic literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines . The litDiagnostic and Statistical Manual of Mental Disorders  criteria. We excluded studies that used alliance measures that were developed for the purpose of a specific study and were not used elsewhere. When more than one assessment of TA was made, we took the first assessment.Our inclusion criteria were as follows: (a) ratings of the TA from both client perspective and therapist perspective had to be reported, (b) studies had to include at least eight individual sessions of psychotherapy, (c) studies had to have a group design of at least 10 participants, (d) patients had to be 18 years of age or older, and (e) studies had to be published in English, (f) over 60% of the subjects had to be diagnosed with schizophrenia spectrum disorders, personality disorders, or substance misuse disorders according to n = 3,647. The initial search yielded 763 articles. Two independent coders conducted the initial screening by examining titles and removing records that clearly did not match the inclusion criteria. Next, each coder examined the abstracts and made a decision as to whether they met the inclusion criteria. In cases of disagreement, or in cases where the abstract did not include enough information to allow agreement, the full text was obtained. This process enabled the identification of 22 studies, We included sample information regarding study year, authors, diagnosis, sample size, alliance measures, effect size, and time of measurement when available, as can be seen in Abbreviations: BSQ, Bern Session Questionnaires; CALPAS: California Psychotherapy Alliance Scale; HAQ, Helping Alliance Questionnaire; SQ: Session Questionnaire; STAR, Scale to Assess the Therapeutic Relationship; WAI, Working Alliance Inventory.n = 3,647). We analyzed the data using a random-effects meta-analytic model with Cohen’s d standardized mean effect size. Further, we conducted moderator analyses with client diagnosis and alliance instrument as potential categorical moderators of the total effect size.We identified 22 records . Heterogeneity analyses produced a significant Q-statistic (Q = 94.96) and a high amount of heterogeneity, as indicated by the I2 statistic (I2 = 77.88%), suggesting that moderator analyses were appropriate. Results indicated a medium effect size for the mean client-therapist difference in their TA estimations , results were Q = 3.7, I2 = 0%, d = .81, and 95% CI = 0.44–1.26, indicating a large effect size for the client-therapist mean difference.Next, we assumed that the measure type could be a moderator that would subdivide the studies’ effect sizes. Fourteen studies used the WAI ; two stuThe present meta-analysis included a total of 22 studies assessing TA by both therapists and clients diagnosed with schizophrenia spectrum disorders, personality disorders, and substance misuse disorders. Consistent with previous investigations of TA among individuals with other mental disorders , we founThe finding that clients tend to estimate their alliance as somewhat higher than do therapists may represent a general psychotherapy bias, evident in both within  and betwOur findings also suggest that the TA measurement type moderates the agreement between client-therapist estimations of the TA. The scale that assesses TA in community mental health care, that is, the STAR , showed The WAI  producedIn sum, it is possible that the reason the STAR (as opposed to the other measurements) yielded no gap between client and therapist estimations was its sensitivity to specific aspects of the TA with individuals who have serious mental illnesses in psychiatric settings. Instruments that are specific and sensitive to population and setting seem to be most appropriate when evaluating dyadic constructs among individuals with severe disturbances. Specifically, it seems that focusing on aspects of openness, trust, and honesty of the therapeutic relationship, and focusing on understanding the subjective meaning of the experiences, contribute to better agreement.The finding that diagnosis did not moderate the agreement between client and therapist estimations of the TA may imply a trans-diagnostic phenomenon. A previous meta-analysis found that the severity of the disturbance as classified mainly according to setting groups moderated TA congruence, but specific diagnosis groups were not assessed . In lineWhen considering the findings of the current meta-analysis, a few limitations should be taken into account. First, we used only one timepoint of assessment of TA (mostly at the beginning of therapy). Recent investigations have highlighted the importance of longitudinally tracking the TA in order to capture the complex dynamics of the dyadic perspective over the course of treatment ,54,58. SWith these limitations in mind, our meta-analysis suggests that clients with serious mental illness tend to have higher estimations of TA than do therapists, a finding that is also often found among clients without such psychiatric disorders. The level of agreement between client and therapist estimations seems to be dependent on the instrument used to assess TA, with no indication of client’s diagnosis moderating effect.When considering agreement on TA, it is important to take into consideration the different aspects of TA that are emphasized in the different TA measurements. In terms of using the TA rating as a means of feedback, it could be beneficial for therapists to take into consideration specific items and concepts of TA when interpreting the meaning of the gaps between them and their clients. Specifically, when relating to more general aspects of TA, therapists can expect to see larger gaps between them than when relating to more context-specific aspects such as trust, openness, and meaning-making of subjective experiences.


The underlying mechanisms of alcohol use disorder (AUD) are regarded to be strongly associated with genetic factors. Although great efforts have been made to identify the association of rs4680 polymorphism in the catechol-o-methyltransferase gene and risk to AUD, the outcomes were still inconsistent. This study is aimed at exploring the association of rs4680 polymorphism and AUD by using a meta-analysis approach.  Literature searching was undertaken across PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. We set the search period before February 20, 2020. We used the Review Manager 5.3 (RevMan 5.3) software to estimate the effect sizes in five genetic models. P = 0.70; VV vs. MM, OR = 0.99, 95% CI 0.79-1.23, P = 0.92; VM vs. MM, OR = 0.91, 95% CI 0.81-1.03, P = 0.15; VV+VM vs. MM, OR = 0.95, 95% CI 0.80-1.13, P = 0.65; VV vs. VM+MM, OR = 1.04, 95% CI 0.91-1.18, P = 0.57. Subgroup analysis by gender suggested rs4680 polymorphism was marginally associated with an elevated risk to AUD among males . However, subgroup analysis by race and diagnosis did not support any significant association.  In total, eighteen case-control studies and two cohort studies were included in this study. The merged results of overall population indicated there was no significant association between rs4680 polymorphism and AUD: V vs. M, OR = 1.02, 95% CI 0.93-1.12,  The present study suggests that rs4680 polymorphism has no association with AUD in the overall population, but it has a weak association with AUD in males. Carriers of VM genotype in males appear to have an increased risk to AUD. Alcohol use disorder (AUD) is a chronic relapsing psychiatric disorder manifested by excessive alcohol consumption, which often results in physical and psychological symptoms . ObsessiEvidence in many studies showed that more than 50% of the risk factor could be attributed to genetic components , 4. The COMT is a protein-coding gene located on human chromosome 22q11.2. Its classical function is to catalyze the transfer of methyl groups from S-adenosylmethionine to catecholamines. This O-methylation leads to the major degradative pathway of the catecholamine transmitters and thus regulates the metabolisms of neurotransmitters dopamine, epinephrine, and norepinephrine. Polymorphisms in COMT may alter its expression level and enzyme activity. The past several decades have seen numerous investigations about the association of rs4680 polymorphisms in COMT and the risk of AUD, but their results are inconsistent. Therefore, the present work is aimed at providing a comprehensive analysis of individual studies and elucidating the correlation of rs4680 polymorphism and AUD susceptibility.We searched Web of Science, PubMed, Embase, Wanfang, and CNKI databases. The search string was  AND (Alcohol Dependence OR Alcohol Addiction OR Chronic Alcoholic Intoxication OR Alcohol Use Disorder OR Alcohol Use Disorders OR Alcohol Abuse OR Alcohol misuse OR Problem drinking OR Harmful drinking OR Alcoholics OR Alcoholism) AND . Language restriction was not posed. The latest search was performed on February 20, 2020.Studies that met the following criteria were included: (1) case-control or cohort studies on rs4680 polymorphism and AUD; (2) studies with available data for calculating odds ratio (OR) and 95% confidence interval (95% CI). Letters, editorials, duplicate studies, and case reports were excluded. All studies were reviewed by two investigators independently. Any discrepancy was resolved by mutual consent.Two investigators abstracted main information from the eligible studies: author's name, publication year, nation, ethnicity, gender, design, diagnostic criteria, sample size, genotype and/or allele distribution, and results of the Hardy-Weinberg equilibrium (HWE) test . The quaQ-statistical test and I2 test to check the between-study heterogeneity. In the condition of P < 0.1, I2 > 50%, the random-effected model was selected. Otherwise, the fixed-effects model was used. Subgroup analyses by ethnicity and gender were performed. Publication biases were assessed by funnel plots.ORs together with 95% CIs were calculated to appraise the association of rs4680 polymorphism and alcohol use disorder under five genetic models including allelic model (V vs. M), homozygous model (VV vs. MM), heterozygous model (VM vs. MM), dominant model (VV+VM vs. MM), and recessive model (VV vs. VM+MM). We used the In total, we identified 705 records. Of them, 180 records were erased because of duplication. After title and abstract screening, 502 irrelevant items were deleted. Of the remaining 43 publications, 23 ineligible publications were excluded based on inclusion and exclusion criteria. Ultimately, 20 articles  remainedThe main characteristics of the included studies are listed in All the studies were in HWE with the exception of the study by Altintoprak et al. . It shouP = 0.70 . However, no significant association was detected under other genetic models. Regarding the females, rs4680 did not appear to be associated with AUD under five genetic models. Besides, subgroup analysis based on diagnosis still did not support any association of rs4680 and AUD. The summarized outcomes are displayed in Subgroup analysis by ethnicity did not find any significant association of rs4680 and AUD in both Asians and Caucasians under any genetic model. Furthermore, we stratified the participants by gender. For the males, a marginally significant association was observed under the heterozygous model (VM vs. MM, OR = 0.81, 95% CI 0.67-0.98, After excluding the studies which were out of HWE, the recalculated effect sizes had no significant change. Therefore, it was not removed from the meta-analysis. The leave-one-out method was used to investigate the effect of an individual study on the pooled ORs and 95% CI. The results did not alter significantly through omitting any single study, indicating the stability of the outcomes. Furthermore, funnel plots did not have substantial asymmetry , suggestNumerous meta-analysis studies have reported the associations of gene polymorphisms and AUD. For instance, Zhang et al.'s study  publisheSNP rs4680 is a famous functional variant in the COMT gene. More than 40% of the enzymatic activity is affected by rs4680 polymorphisms. Numerous psychobiological disorders and clinical symptoms were proved to be associated with COMT gene polymorphisms. Gervasini et al.'s study  suggesteIn the present work, we included 20 articles worldwide, of which 3 studies were from China. Most of these studies showed that there was no statistically significant association between COMT gene polymorphisms and AUD risk. After combining the results of all included studies, the pooled meta-analysis results remained the same. We also conducted the subgroup analysis divided by ethnicity and gender; all the results were turned out to be negative. Therefore, we could only come to a conclusion that there was no association between COMT gene polymorphisms and alcohol dependence risk.COMT was first reported in 1958 . COMT haCOMT mainly prevails as an S isoform in the cytoplasm. It is widely distributed in most tissues including the liver and pituitary gland, cerebellum, lungs, mammary glands, etc. , 43. GuaP value for the HWE test of one included study is <0.05, which means that the included participants of this study may not be representative. Last but not the least, we only searched the online databases in English and Chinese; relevant articles written in other languages were not included in this work, which may lead to selection bias.Some drawbacks of the present work should not be neglected. First, although we have gathered the most comprehensive original studies on this issue worldwide, the study number and the sample size are relatively small and thus may lead to a possibility of false negative. Second, it is clear that COMT polymorphisms have significant impact on the enzyme activity. However, we did not found any association between rs4680 polymorphism and AUD susceptibility in the overall population; the underlying mechanisms are yet an unanswered question. Third, the occurrence of AUD is thought to be determined by the combined effects of the intrinsic factor and environment factor; we only concentrated on the genetic influences. Fourth, the The present study suggests that rs4680 polymorphism has no association with AUD in the overall population, but it has a weak association with AUD in males. Carriers of VM genotype in males appear to have an increased risk to AUD. Considering the limitations of this study, future well-designed studies with large sample sizes are encouraged.


Background: Both meta-analyses and systematic reviews were used to assess the relationship between purinergic receptor P2X ligand-gated ion channel 7 (P2RX7) rs3751143 polymorphism and the risk of cancer.Materials and methods: The data used in this research were collected from Google Scholar, Web of Science, CNKI, and Wan Fang Data databases. The final retrieval ended on 22 February 2019. The strength of correlation was assessed using odds ratios and 95% confidence intervals. Based on the heterogeneity test results, fixed-effect (Mantel–Haenszel) or random-effects (DerSimonian–Laird) models were selected to summarise the collective effects.Results: Eight separate studies containing 1462 cancer cases and 3037 controls were enrolled. Overall, there was no significant association between P2RX7 rs3751143 polymorphism and the risk of cancer in the allelic, homozygous, heterozygous, dominant, or recessive models.Conclusions: Our meta-analysis indicates that there is no significant association between P2RX7 rs3751143 polymorphism and the risk of cancer in the allelic, homozygous, heterozygous, dominant, and recessive models. According to the studies, one in four people in the United States died of cancer . In rece.  demonstrP2X7 gene, also known as the P2RX7 gene, is located on chromosome 12, a highly polymorphic gene with more than 11 polymorphisms that have specific impacts on P2RX7 function, including loss of function or feature enhancement [P2RX7 polymorphisms are clinically critical in various diseases, including tumors [P2RX7 polymorphism in tuberculosis and mood disorders [. [P2RX7 gene (Glu496Ala and Gly150Arg) are linked to an increased risk of osteoporosis. Gadeock et al. [P2RX7 genetic polymorphisms and organic cation uptake in human myeloid leukaemia kg-1 cells, and they found that these functional polymorphisms can result in the verification of the survival and invasiveness of myeloid leukaemia cells.The ancement . Furtherg tumors ,10. Someisorders . Wesselik et al.  demonstrP2RX7 rs3751143 polymorphism and the risk of cancer.Thus far, most studies have only focussed on the non-synonymous polymorphism rs3751143 , which was identified as the highest associated polymorphism in two published studies . The 151P2RX7 OR P2X7) AND (polymorphism OR mutation OR variation OR single nucleotide polymorphism OR genotype) AND .The data in this research were obtained from Google Scholar, Web of Science, CNKI, and Wanfang databases. The final retrieval ended on 22 February 2019 using the following retrieval types:  case–control design, (3) extracting genotype and allele frequencies to calculate advantage odds ratio (OR) and 95% confidence interval (CI), and (4) full-text articles published in English or Chinese. The major exclusion criteria were as follows: (1) case report, case-solo, or retrospective studies and (2) studies without primary data on P2RX7 polymorphisms (or contact with the corresponding author still did not achieve the necessary raw data).Articles that satisfied the following inclusion criteria were included in the current study: (1) studying the relationship between P2RX7 polymorphisms from each study. If no there was no raw data in the related articles, an additional data request was sent to the corresponding author.Two reviewers extracted data independently using standard protocols, and the results were reviewed by a third reviewer . These distinctions were resolved through a discussion with the research team. We extracted data on the first author, publication year, journal, ethnicity, type of cancer, number of cases, control groups, and available genotypes and allele frequencies for the Q-test based on the chi-square test. The Hardy–Weinberg Equilibrium (HWE) of the control group was calculated using the chi-square test. Sensitivity analysis was used to evaluate the stability of the results, and the publication bias was evaluated using Begg’s funnel plot and Egger’s test. Statistical significance was set at P<0.05. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method of the present study is shown in Supplementary Table S1 [Statistical analyses were performed using STATA version 12.0 . ORs and 95% CIs were used to evaluate cancer susceptibility. In addition, pooled ORs of the following five genetic models were computed: allelic contrast, heterozygote, homozygote, dominant, and recessive models. The heterogeneity of various studies was measured using a Table S1 .P2RX7 polymorphisms that were not studied in other independent studies, resulting in the impossibility of data pooling; and four articles failed to provide sufficient data for calculation. Therefore, we eventually enrolled eight articles in this meta-analysis [As shown in analysis ,20,24–29P2RX7 gene rs3751143 polymorphism and four cancer types . The ethnicities included Caucasian (four studies), Asian (three studies), and mixed . The control sources were all hospital-based (H-B) sources. According to the Newcastle–Ottawa Scale (NOS), five articles were of high quality (NOS score: 7–9) and three articles were of moderate quality (NOS score: 5–6) (Supplementary Table S2). All studies reported the number of corresponding genotypes for both the cases and control groups as recessive, heterogeneous, and wild genotypes.The eight enrolled articles consisted of eight case–control studies with P2RX7 rs3751143 polymorphism. Overall, analyses showed that no evident risk of cancer in the allelic, homozygous, heterozygous, recessive, and dominant models.The pooled ORs and corresponding 95% CIs are shown in P2RX7 rs3751143 polymorphism and the risk of cancer.With regard to the stratification analysis by ethnicity, genotyping method, and HWE status, the results were consistent with the overall result that there was no correlation between P>0.05).This meta-analysis was repeated and we omitted each study individually to test the effectiveness of all eligible studies included in our study. The results indicated no substantial change in the set ORs corresponding to rs3751143 polymorphism (Supplementary Table S3). Publication bias was assessed using funnel plots generated by STATA 12.0. Any obvious asymmetry was hardly observed . We furtP2RX7 has been investigated for its role in conferring susceptibility to various emotional disorders. It is located in 12q24 and contains 13 exons spanning the 53-kb region [P2RX7 encodes a purinergic receptor involved in the Ca2+-dependent signalling pathway. Its expression in the brain regulates immune function and neurotransmitter release [P2RX7 has a significant tumour growth-promoting effect in vivo. Fu et al. [P2RX7-mediated apoptosis activation inhibits the development of DMBA/TPA-induced mouse papilloma and cancer. However, P2RX1, P2RX7, P2RY12, P2RY13, and P2RY14 were relatively downregulated in lung cancer tissues and were associated with a favourable prognosis [b region . P2RX7 e release ,32. Acti release  found thu et al.  also shorognosis .Due to their high density, scalability, and genome-wide distribution, SNPs are considered ideal genomic resources in genetic studies for the characterisation of genetic resources and functional gene identification for traits . ConsideP2X7R gene have been described to influence the function of this receptor, including loss or gain of function [P2X7R SNPs with amino acid changes, rs3751143 , rs2230911 , and rs7958311 , have been shown to result in a loss of receptor function in both channel and pore function [P2RX7 receptor function [et al [P2RX7 genotypes of 121 patients with CLL and correlated these findings with a broad range of clinical parameters, and their results indicated that P2RX7 polymorphism of 1513 A to C is unlikely to play a vital role in the pathogenesis or progression of CLL. Hence, the incidence of this variation and its relevance to the pathogenesis of CLL is unclear. However, Thunberg et al. [P2RX7 polymorphisms may affect sputum metabolism and play a critical role in the development of liver cancer. Duan et al. [P2RX7 rs3751143 polymorphism and susceptibility to liver cancer in the Chinese Han population. Their results indicated that P2RX7 rs3751143 polymorphism is associated with an increased risk of developing HCC.SNPs in the function . Song etfunction . For insfunction ,40. In pfunction . Conversn [et al . analyseP2RX7 rs3751143 polymorphism and the risk of cancer in any of the genetic models was observed.In recent years, research related to cancer has focused on many candidate genes. However, the results of the surveys are inconsistent. To obtain sufficient detection capabilities, a large number of sample subjects is required. The lack of statistical ability in small-sample association studies may lead to contradictory results. Meta-analysis of mental illness has become critical due to the rapid rise in the number and size of datasets. In the present study, no significant association between In the current meta-analysis, several specific details are worth considering. First, this meta-analysis only included published studies, which may have publication bias. Second, the results of the meta-analysis may be distorted by the discovery of significant heterogeneity between studies in some comparisons. Third, our results are based on unadjusted estimates and, if a more accurate analysis by age and sex are available in individual data. Finally, all eligible studies included Caucasian populations.P2RX7 rs3751143 polymorphism and the risk of cancer. Given the inconsistencies in the subgroup analysis of different types of cases, further studies including larger sample sizes are needed.In summary, our meta-analysis showed no significant association between Click here for additional data file.


Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of death worldwide. Incidence rates vary internationally, with the highest rates found in Southern and Eastern Africa, and central Asia. Initial studies identified multiple factors associated with an increased risk of ESCC, with subsequent work then focused on developing plausible biological mechanistic associations. The aim of this review is to summarize the role of risk factors in the development of ESCC and propose future directions for further research. A systematic literature search was conducted to identify risk factors associated with the development of ESCC. Risk factors were divided into seven subcategories: genetic, dietary and nutrition, gastric atrophy, infection and microbiome, metabolic, epidemiological and environmental, and other risk factors. Risk factors from each subcategory were summarized and explored. This review highlights several current risk factors of ESCC. Further research to validate these results and their effects on tumor biology is necessary.Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of death worldwide. Incidence rates vary internationally, with the highest rates found in Southern and Eastern Africa, and central Asia. Initial observational studies identified multiple factors associated with an increased risk of ESCC, with subsequent work then focused on developing plausible biological mechanistic associations. The aim of this review is to summarize the role of risk factors in the development of ESCC and propose future directions for further research. A systematic search of the literature was conducted by screening EMBASE, MEDLINE/PubMed, and CENTRAL for relevant publications. In total, 73 studies were included that sought to identify risk factors associated with the development of esophageal squamous cell carcinoma. Risk factors were divided into seven subcategories: genetic, dietary and nutrition, gastric atrophy, infection and microbiome, metabolic, epidemiological and environmental and other risk factors. Risk factors from each subcategory were summarized and explored with mechanistic explanations for these associations. This review highlights several current risk factors of ESCC. These risk factors were explored, and explanations dissected. Most studies focused on investigating genetic and dietary and nutritional factors, whereas this review identified other potential risk factors that have yet to be fully explored. Furthermore, there is a lack of literature on the association of these risk factors with tumor factors and disease prognosis. Further research to validate these results and their effects on tumor biology is absolutely necessary. Squamous cell carcinoma of the esophagus (ESCC) is an aggressive condition that ranks seventh in incidence and sixth in mortality among all malignancies worldwide. It is the more prevalent histological variant of the two main types of esophageal cancers. There is a clear geographic variation in the distribution of ESCC globally. The prevalence is higher in east Asia, eastern and southern Africa, as well as southern Europe, while it is lower in North America and other parts of Europe. This geographical variation is clearly demonstrated as the annual incidence in the United States is 3.5/100,000 persons, while it is significantly higher at 115/100,000 in countries such as Iran. Such epidemiological differences have led to an evaluation of specific risk factors that predispose patients to the development of ESCC. Initial observational studies identified lifestyle factors such as diet, smoking, and obesity to be associated with an increased risk of ESCC. Subsequent work then developed mechanisms to explain these relationships at a molecular level, which subsequently led to further elaboration of other less obvious yet more permeating risk factors. This review aims to summarize the role of risk factors in the development of ESCC and propose areas of future research.A systematic search of the literature was carried out of the following electronic databases: MEDLINE/PubMed (1966 to April 2020), EMBASE (1980 to April 2020), and the Cochrane Central Register of Controlled Trials (CENTRAL) from The Cochrane Library  on the 29 July 2020. The search strategy for this review was constructed for each database by using a combination of medical subject headings (MeSH) and free-text terms.Reference lists of selected articles were also examined to identify relevant studies that were not identified in the database searches. In addition, the World Health Organization International Clinical Trials Registry, ClinicalTrials.gov, ISRCTN Register and PROSPERO were searched to identify ongoing and unpublished studies.The inclusion criteria were studies describing and evaluating the strength of association of risk factors within ESCC. All randomized controlled trials (RCTs) and observational studies, adult only studies, human studies, English studies, and studies where the patients had ESCC were included.The exclusion criteria were pediatric studies, non-human studies, non-English studies, non-ESCC studies, case series, case reports, editorials, conference abstracts and opinions.One author (MT) independently reviewed all studies identified by the search strategy. After removing duplicates, the titles and abstracts of the studies were screened for inclusion using Covidence software . Where tTwo authors  independently extracted data from the included studies using an electronic data extraction spreadsheet. Disagreements were resolved through discussion and where consensus could not be reached, a third independent author (SRM), was consulted.The primary outcome was identifying risk factors associated with ESCC. Risk factors were divided into seven subcategories: genetic, dietary and nutrition, gastric atrophy, infection and microbiome, metabolic, epidemiological and environmental, and other risk factors.The literature search identified 21,071 studies. After removing duplicates, 19,154 abstracts were assessed for eligibility. Following abstract screening, 18,990 studies were excluded based on title and abstract relevance. Of the remaining 146 articles, 73 studies met the inclusion criteria. PRISMA flowchart summarizing the search strategy is demonstrated in The role of genetic factors in the development and prognosis of ESCC is an area that has been widely studied, but yet remains rather limited in its understanding. Unlike other malignancies of the GI tract such as colorectal cancer, ESCC does not have a well-established tumorigenesis pathway. However, there are many candidate genes, including silencing mutations of the p53 gene (Tp53). Tp53 is a tumor suppressor gene located at chromosome 17q and is implicated in the early pre-malignant processes of ESCC along with several other cancers. Alterations in p53 expression are often elevated, even in benign conditions such as esophagitis, which later leads to overt malignancy in the minority of patients. In other studies, a direct comparison of p53 expression in histologically cancerous and normal esophageal mucosa was higher in the former ,3. ChangLoss of heterozygosity (LOH) is a common genetic event in cancer development. It encompasses a reduction in the number of copies of a chromosome, deletion of part of a chromosome, and homologous recombination events. LOH is strongly associated with the loss of the wild-type allele in patients who carry a germline mutation and have an inherited cancer syndrome. In esophageal cancer, studies have identified certain chromosomal regions that have exhibited LOH. For example, in a small study of 11 subjects, Hu et al. carried out genome wide scans using 366 microsatellite markers and identified 14 chromosomal regions with high frequency LOH exceeding 75% ,9. AllelMalignancies are a motif in many genetic syndromes, including esophageal cancer . For exaThe influence of genetic factors is not only limited to the development of ESCC, but also to how the cancer is handled by the body. One aspect of this involves genetic polymorphisms, which account for variation in cancer outcomes between individuals. For example, polymorphisms of LPM2-60 and LMP7-145 have been shown to generate functional alterations in how tumor antigens are processed in colorectal and gastric cancers . For exaDNA methylation is a main form of epigenetic inheritance and is often used as a biomarker for tumor classification, diagnosis, and prediction of metastasis or recurrence. An increase in the methylation of CpG islands in the promoter region of tumor suppressor genes (TSGs) can reduce their transcription and thus the function of TSGs. Such a phenomenon is termed epigenetic silencing and is a common molecular aberration in ESCC . Paired Micro RNAs (miRNA) are small, single stranded non-coding genetic sequences with functions in RNA silencing and post-transcriptional modulation of genetic expression. In tumorigenesis, oncogenic miRNAs are often upregulated, while tumor-suppressing miRNAs are usually downregulated. For example, miR-508 inhibits several phosphatases such as PTEN in the PI3K–AKT pathway and results in metastasis of ESCC cells . The oveDietary habits have been implicated in the development of ESCC. 19 studies have showed that a ‘healthy diet’ may be protective against ESCC whereas a more ‘western diet’ may increase the risk.One of the main components of a ‘healthy diet’ is intake of vegetables and fruits. Seven studies have shown that reduced vegetable and fruit intake along with a low fiber diet increases the risk of ESCC ,28,29,30Cheng et al. reported an increased risk of ESCC with a high intake of salted and pickled food . ConsumpRegarding a ‘western diet’ that is mainly meat and fat based, four studies have shown an association between an increase in meat and dietary fat intake with an increased risk of ESCC ,30,34,35Reduced dietary intake of nutrients and vitamins have been associated with an increased risk of ESCC ,38. The Nutrition indices have also been shown to be predictors of risk in ESCC, namely, glycemic index (GI), glycemic load (GL), and dietary inflammation index (DII) in three studies ,40,41. GSun et al. reported that an increase in consumption of low-quality water was found to increase the risk of ESCC . FurtherEarly cohort studies observed that patients not exposed to the classic risk factors such as alcohol, smoking, or processed foods still developed esophageal cancer, suggesting the possibility of other non-classical factors. This was promptly followed by work that linked gastric atrophy to cytotoxin-associated gene A (CagA)-positive Helicobacter pylori (H Pylori) and autoimmune conditions such as pernicious anemia, and subsequently gastric atrophy to ESCC . In one The role of infectious agents as a risk factor for ESCC is poorly understood, unlike adenocarcinoma of the esophagus where H Pylori is a well-established causative agent. One way to approach this would be to classify causative pathogens as part of the internal human microbiome, and external agents in the environment that infect patients. Typically, Streptococci are the dominant microorganisms found in the esophagus, although this is altered in disease, including premalignant conditions such as esophagitis . For exa2), acetaldehyde, and retinoid metabolism [2 plays a central role in the Sammon and Alderson model of esophageal carcinogenesis described in 1998 [2 in ESCC carcinogenesis [2 has a direct stimulatory effect on cell division. This result points to a potential positive feedback loop in which PGE2 stimulates COX2 levels, leading to further metabolism of maize-derived linoleic acid into PGE2 leading to further stimulation of cell division. The direct mitogenic action of PGE2 supports the hypothesis that increased PGE2 in gastric fluid may be a risk factor for ESCC.Five studies focused on mechanistic pathways and end metabolites in ESCC identified pathways of interest, namely: Prostaglandin E2  deficiency is known to be an independent risk factor of early ESCC. This association was mainly seen in hypochlorhydric patients. This raises the possibility that acetaldehyde metabolism in an anacidic stomach may be involved, at least in some capacity, in the ALDH2 related risk to ESCC ,55. AlteESCC rates vary greatly between and within countries. Geographical and environmental factors have been identified as possible reasons for this. Geographical high-risk areas have been categorized into two bands: the central Asian esophageal cancer belt extending across central Asia from the Caspian Sea to northern China, and the second band extending from Eastern to Southern Africa ,59.Two studies on environmental risk factors mainly hypothesized that trace element imbalance in the soil may be a risk factor of ESCC ,60. The The primary source of fuel in poorer communities in Africa, Asia, and South America—high-risk regions of ESCC—is solid biomass fuels from wood, charcoal, coal, dung, and crop residues. A systematic review and meta-analysis of 16 case-control studies concluded that biomass fuel is associated with significantly higher risks of ESCC . PolycycThere are 11 further studies that have dissected other less common risk factors for the development of ESCC. Ionizing radiation has been postulated as a causative factor, although the evidence for this is not concrete. In the United Kingdom, it is estimated that less than 1% of esophageal cancer is linked to radiation, and ESCC accounts for an even smaller percentage of these cases. Broadly, sources of radiation can be classified as iatrogenic and non-iatrogenic, with the latter being predominantly due to occupational reasons. For example, in patients who received radiotherapy for treatment of breast cancer, the five year incidence of ESCC in the upper and middle thirds of the esophagus was increased ,63. ThusOther risk factors that play a minor role include caustic injury to the esophagus , head and neck tumors, previous endoscopic resection of ESCC and achalasia. Achalasia is a relatively rare condition with an annual incidence rate of 0.5–1.2 per 100,000 individuals, but it is associated with a higher risk of ESCC . For exaOther studies have scrutinized the incidence of head and neck cancers in patients who also developed ESCC, and attributed this association to the shared lifestyle risk factor of excess smoking and alcohol use . In patiThe literature search identified two ongoing studies. Both study designs are case-control studies. One study is based in Malawi and aims to investigate multiple risk factors for ESCC, including HIV infection, polycyclic aromatic hydrocarbons exposure, dietary factors including fumonisin and selenium, scalding hot beverages and foods, and tobacco and alcohol consumption. The study is due to complete in December 2021 and aims to recruit 600 participants . The othThis review highlights current risk factors of ESCC. Factors identified mainly focused around seven subcategories: genetic, dietary and nutrition, gastric atrophy, infection and microbiome, metabolic, epidemiological and environmental, and other risk factors. These risk factors were explored, and explanations dissected. Most studies focused on investigating genetic, dietary, and nutritional factors, whereas this review identified other potential risk factors that have yet to be fully explored. Furthermore, there is a lack of literature on the association of these risk factors with tumor factors and disease prognosis. Further research to validate these results and their effects on tumor biology is required.


Helicobacter pylori prevalence in Southwest China during recent period through a systematic review and analysis.This epidemiological research will be aimed to evaluate the longitudinal changes of H pylori infection will be estimated. In the individual city, the longitudinal comparisons will be conducted to evaluate the trends referring to the earliest cross-sectional baseline. The risk ratio and its 95% confidence interval will be estimated. Subgroup analyses will be performed in sex-specific and age-specific subsets. Trend analysis for proportions (p for trend) will be estimated in the longitudinal evaluation. If applicable, the longitudinal clearance rate (%) will be estimated.The database PubMed and China National Knowledge Infrastructure will be searched. The cross-sectional studies or cohort studies on either massive or hospital-based health checkup population will be potentially eligible. The study population was originated from one of the southwestern major cities, Chengdu (Sichuan), Chongqing, Kunming (Yunnan), Guiyang (Guizhou), or Lhasa (Tibet). Two reviewers will independently select studies, extract data, and assess the quality of studies. The prevalence of The ethical approval is not required due to the nature of literature-based research. The results will be disseminated through meetings and a peer-reviewed journal.CRD42019120764 The infection of Hp was suggested as an important risk factor for gastric cancer in both western and eastern countries.–4 Although gastric cancer was relatively rare in Germany, the strong association between Hp infection and gastric cancer risk was confirmed in a population-based longitudinal cohort. Massive Hp screening and eradication were organized in Japan and South Korea as a fundamental approach to identify high-risk subpopulation and prevent occurrence of disease. Understanding the prevalence of Hp might be helpful to population-tailored screening and eradication strategy to prevent gastric cancer.Since 1994, the World Health Organization has defined  and led to heavy burden of high mortality due to low proportion of early diseases.,9 Southwest China is a less developing region with multiple ethnics, accounting for 24.5% of China's land area and 14.1% of total population  OR “helicobacter pylori”[All Fields]) AND (sichuan[All Fields] OR chengdu[All Fields] OR chongqing[All Fields] OR yunnan[All Fields] OR kunming[All Fields] OR guizhou[All Fields] OR guiyang[All Fields] OR tibet[All Fields] OR xizang[All Fields] OR lasa[All Fields] OR lhasa[All Fields] OR (west[All Fields] AND (“china”[MeSH Terms] OR “china”[All Fields])) OR (western[All Fields] AND (“china”[MeSH Terms] OR “china”[All Fields])) OR (southwest[All Fields] AND (“china”[MeSH Terms] OR “china”[All Fields])) OR (southwestern[All Fields] AND (“china”[MeSH Terms] OR “china”[All Fields]))).” Similarly, the literature search will be performed in the China National Knowledge Infrastructure database of Chinese academic journals through the similar strategy. Those nonjournal data of our institute West China Hospital, a central teaching hospital in Sichuan, will be additionally included. The publication language in English or Chinese will be acceptable.2.213C-urea or 14C-urea), or serological IgG test among observations. There should be no limitation in age, sex, and ethnics of observations.The cross-sectional studies or cohort studies on either massive or hospital-based health-checkup population will be potentially eligible. Those studies which contained or were contaminated with gastric malignancies will be excluded. Those researches on healthy persons in an experimental setting instead of health checkup will be also excluded. The study population was originated from one of the southwestern major cities, Chengdu (Sichuan), Chongqing, Kunming (Yunnan), Guiyang (Guizhou), or Lhasa (Tibet). The prevalence of Hp infection was tested by any method including breath test /prevalencei) and (j) were sequential age groups with a 10-year interval.The STATA 14.0 softwares will be used for statistical analysis. The prevalence (%) of Hp infection and its 95% confidence intervals will be estimated. In the individual city, the longitudinal comparisons will be conducted to evaluate the trends referring to the earliest cross-sectional baseline. The risk ratio and its 95% confidence intervals will be estimated. Subgroup analyses will be performed in sex-specific and age-specific subsets. Trend analysis for proportions (p for trend) will be estimated in the longitudinal evaluation. In addition, if applicable, the longitudinal clearance rate (%) will be estimated as Clearance (%) = [.2.8 and a flow diagram will be drawn.This systematic analysis will be conducted according to the MOOSE 2000 statements,2.9The results will be disseminated through meetings and a peer-reviewed journal.3,16 Because of the diversity of economics, ethnics, and lifestyles,,18 it should be meaningful to investigate the tailored prevention and screening plan for cancers. As known, the Hp infection is an identified risk of gastric cancer.,20 In addition, Hp infection might be an potential risk factor for the development of pancreatic or colorectal cancers.,22 Therefore, the present study is aimed to observe and analyze the longitudinal changes of Hp prevalence in Southwest China during recent periods. The Sichuan Gastric Cancer Early Detection and Screening project was based on an investigator-driving group in West China Hospital of Sichuan University. Serial researches are conducted under the Sichuan Gastric Cancer Early Detection and Screening project to provide information for the tailored screening of gastric cancer in Sichuan province, even in Southwest China.,18,23,24 For example, the prevalence of Hp was quite high up to >80% among Tibetans in decades ago, but the epidemiologic changes and status in recent years might be informative to design the Hp screening and eradication protocol in Tibetans. Optimal or cost-effective screening and eradication protocol is able to reduce the gastric cancer incidence and related mortality.,26 Compared to the experiences of gastric cancer prevention and control in Japan and Korea,,27–29 a lot of researches on etiology, high-risk population, screening, and surveillance protocol and economics are fairly required in China. The evidence-based conduction of gastric cancer prevention and control would be believably organized in the future.Health burden resulted from digestive system cancers was still heavy in China, especially the gastric cancer–related high mortality.The work was based on the Sichuan Gastric Cancer Early Detection and Screening (SIGES) project. The authors thank the substantial work of Volunteer Team of Gastric Cancer Surgery (VOLTGA), West China Hospital, Sichuan University, China.Conception, registration, literature search, and research conduction: Rui Wang.Literature selection, data extraction, and quality assessment: Dan Bai, Wen Xiang, Yu-Feng Zhang, Kun-Yi Ba.Conception, analysis, interpretation, writing, and academic inspection: Xin-Zu Chen.


Background: Previous studies have suggested that serum total bilirubin (STB) levels are associated with heightened chronic kidney disease (CKD) and mortality in both the general population and nephropathy patients. However, these results remain inconsistent. The aim of our study was to investigate whether STB was a predictor for progression of CKD and mortality by meta-analysis.Methods: We performed a systematic literature search in PubMed, Web of Science, MEDLINE, EMBASE, Google Scholar, and Cochrane Library's database up to June 30, 2019. Pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) were extracted for the highest vs. lowest category STB levels within the physiological range, and a random-effects model was applied to calculate the dose–response relationships. A pooled hazard ratio (HR) was used to investigate the association between STB levels and mortality in dialysis patients.Results: A total of 16 studies, wherein participants were followed from 21 months to 7 years, were eligible for inclusion in the study. For the categorized STB, 11 studies with 41,188 participants were identified and analyzed. Patients with the highest STB levels were associated with a lower risk of CKD  compared to those with the lowest STB levels. Furthermore, based on seven studies, a pooled RR of 0.89, 95% CI (0.80–0.99) was observed for the continuous STB levels (per 0.2 mg/dL increase). Four studies that included 51,764 participants illustrated that there was no association between STB levels and all-cause mortality . A prominent negative linear relationship  was found between STB levels and risk of CKD. Subgroup analyses showed that there were no significant differences in the subgroup adjustment factor except for sample size.Conclusions: Elevated STB levels within a physiological range are associated with lower risk of CKD regardless of the study characteristics and coincide with a liner dose–response relationship. However, whether high STB levels are a protective factor against mortality remains inconclusive. Large-scale randomized controlled trails are needed to target STB levels for predicting renal outcomes. Chronic kidney disease (CKD), also called chronic kidney failure, is on the rise, and it has become one of the most common complications worldwide. It not only increases the risk of cardiovascular disease and can often progress to end-stage renal disease (ESRD), but it is also related to premature mortality. According to the 2013 Global Burden of Disease Study, CKD ranked 36th in the causes of total number of global deaths in 1990, but rose to 19th in 2013  . PubMed,2 by using the CKD-EPI equation.The inclusion criteria was as follows: (1) the studies investigated the relationship between bilirubin concentration and kidney disease progression, (2) cohort study or random clinical trials, (3) a comparison between highest STB group and lowest STB group or per unit STB increase, (4) followed participants for at least 12 months, (5) reported any of the following renal outcomes: progression to CKD or all-cause mortality, and (6) Relative risk (RR) with 95% confidence intervals CIs or the minimum information necessary to calculate these values were provided as effect size. Liver dysfunction which could lead to elevated levels of serum bilirubin were excluded in original research studies. Studies in review, editorials, letters, and case report forms were excluded from our meta-analysis. If the study did not meet the included criteria and could not provide categories of bilirubin or sufficient data to calculate effect size, then they were also excluded. The categorization for STB levels and the units used were in line with the definition in each study. In order to keep the unit of all included studies in accordance, μmol/L was converted to mg/dL divided 17.1. CKD was defined as a decline in estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 mAll included studies were independently identified by two investigators (JL and ZSL). Data extracted included age, sex, country of origin, study design, populations, serum bilirubin, follow-up, sample size, smoking status, body mass index, No. of cases, outcome, adjusted HR or RR or OR per unit of increase in baseline serum bilirubin, and those for highest and lowest group of STB levels. The studies which had several estimates adjusted HR for different numbers of potential confounders; the greatest number of potential confounding factors was selected for analysis. The quality of all included studies was assessed by two reviewers (JL and ZSL) using the Newcastle-Ottawa scale (NOS). The scores “7–9,” “4–6,” and “1–3” were considered as “high,” “moderate,” and “low” quality, respectively. Any discrepancies between the two investigators were discussed with a third independent reviewer (DWL).2, doubling of serum creatinine, or 50% decline of kidney function or end-stage renal disease (ESRD)] and the secondary outcome was assessment of all-cause mortality in patients who developed CKD and underwent hemodialysis or peritoneal dialysis. The forest plots illustrate the two outcomes reproduced from the individual studies and the size of the symbol for the estimate is proportional to the weight of each study. A dashed vertical line and diamond at the bottom of the forest plot highlights the overall estimate and its 95% confidence interval.There were two outcomes included in this meta-analysis. The primary outcome was the assessment of kidney disease progression to CKD [defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 mQ-test and I2 were used to assess the heterogeneity among studies. Subgroup analysis and meta-regression were performed due to the potential impact of covariates on study heterogeneity . Sensitivity analysis was also conducted by omitting each study one by one. Begg's test and Egger's test were used to evaluate publication bias. STATA and R software were used for statistical analyses and two-sided P < 0.05 was considered to be statistically significant.In our study, the pooled RRs and 95% CIs were used for the association of STB with the risk of CKD and mortality. The hazard ratios (HR) and odds ratio (OR) in some original studies were assumed to provide accurate estimates of the risk ratio, so it was directly considered as RR . After cA total of 2,683 studies were screened from the databases described above, and 16 publications , 20–28 . The chaI2 = 43.8%, P = 0.04) was found, this also demonstrates the association between the STB and the progression to CKD. The RR for per 0.1 mg/dl increases in serum bilirubin were extracted from seven studies that included 10 data points, and were used for continuous variable analysis. Considering clinical experience, each 0.1 ml/dl increase is of little significance, so we calculated the risk ratio (RR) for 0.2 mg/dl increases .The association of STB levels with risk of kidney disease progression were analyzed by the RR of the highest STB levels compared to the lowest STB levels in 11 studies (14 data points). The results highlighted that patients with the highest STB levels were associated with lower risk of CKD progression , as shown in ncreases . To elabAll-cause mortality was extracted from only four studies, including 51,764 patients. The adjusted HR of all-cause mortality for highest STB levels compared to the lowest STB levels was 0.77 (95% CI 0.42–1.41) in dialysis patients with heterogeneity at 84% . Two of Begg's and Egger's test were performed for 11 studies on association of STB levels with disease progression. The results show that publication bias did exist, and trim and fill methods were adapted to adjust for the publication bias , 3. SensP = 0.06, 0.84, 0.55, respectively). Although there were significant differences in sample size >1,000 and <1,000 of the groups, the association between the STB levels and risk of CKD were both significant. We also conducted a regression analysis to evaluate the reason for the association between STB levels and all-cause mortality. There were no significant differences in the subgroup adjustment for albumin, diabetes mellitus, or eGFR except for sample size (P = 0.04)  . The neg = 0.04) .2 = 14.70; P < 0.001). The overall RR per 1 mg/dl increasement was associated with a 20% reduction in risk of CKD (95% CI 0.72–0.90), P < 0.001). No significant heterogeneity among the included studies was found   .Recently, many studies have revealed that STB levels play a critical role in CKD progression and mortality, but other studies have had inconsistent conclusions. Whether or not lower STB levels could be a biomarker of reduced kidney function is currently unclear. As far as we know, this is the first meta-analysis to focus on both CKD progression and all-cause mortality. Our meta-analysis demonstrates that higher STB levels may serve as protective factors for the development of CKD and elevated STB levels could lead to 36% of a significant decrease in the risk of CKD progression. However, the meta-analysis also concluded that there was no significant relationship between STB levels and risk of all-cause mortality.Serum bilirubin has long been recognized as an abnormal sign of liver dysfunction. Recent data strongly indicates that slightly increased STB concentration can be a potent biological protective marker. In humans, low (<7 mmol/L) STB levels may be a risk factor for systemic diseases associated with increased oxidative stress, such as cardiovascular diseases (CVD) , diabetein vitro or in vivo  were used to certify the dose–response relationship.Nonetheless, there are potential limitations to this study. First, our meta-analysis was restricted to published aggregate data. Individual participant-level data were not available, which is the primary limitation of this meta-analysis. Unpublished data or incomplete retrieval of identified studies led to an incomplete set of evidence and produced biased effects in the summary results. Funnel plot and “trim and fill” methods were used for assessment to balance out the publication bias and the relationship between the STB levels, and the risk of CKD remained statistically significant. Second, the included studies do not directly report on the data information required for meta-analysis, which can cause reporting bias. Third, potential confounding factors, such as age, sex, history of smoking, and/or alcohol intake , could not be excluded. The studies did not adjust for same risk factors. Considering this fact, we included these factors in the multiple adjust models as much as possible. Fourth, only a few studies have differentiated the conjugated bilirubin and unconjugated bilirubin, and therefore the accurate role of separating bilirubin could not be investigated. Fifth, only STB levels in a narrow range  were studied. To translate these findings to clinical practice, future studies are needed to define an optimal range of STB. Finally, there was only one study involving a European population, which makes it difficult to definitively assess the association between STB levels and CKD in American and African populations.In conclusion, our study indicates that individuals with reduced bilirubin concentrations, in the absence of liver pathology, are at a higher risk of CKD. This association was confirmed to be a linear dose–response relationship. Whether high STB levels serve as a protective factor of mortality or the risk of renal replacement therapy among the patients that underwent dialysis remains inconclusive. High-quality randomized controlled trials are needed to target STB levels for predicting renal outcomes. Considering that multiple mechanisms likely explain the protective properties of bilirubin and that bilirubin measurement is performed routinely for most patients, bilirubin might be a potential predictor for renal prognosis. It also highlights the importance of monitoring biomarkers related to serum bilirubin homeostasis in early prevention, diagnosis, and treatment of CKD and provides evidence to further multicenter validation research for bilirubin levels in routine risk stratification of CKD.JL: conceptualization, formal analysis, methodology, software, and writing—original draft. JL, DL, and ZL: data curation. DL and ZL: investigation and supervision. ZL: project administration, validation, and writing—review and editing. All authors contributed to the article and approved the submitted version.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.


The impact of albumin-to-alkaline phosphatase ratio (AAPR) on prognosis in cancer patients remains uncertain, despite having multiple relevant studies in publication.Cochrane Library, PubMed, and Web of Science) updated to May 24th, 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed and synthesized using STATA 14, values were then pooled and utilized in order to assess the overall impact of AAPR on patient’s prognosis.We systemically compiled literatures from 3 databases  suggested that decreased AAPR had adverse effect on overall survival (OS). Similarly, pooled results from both univariate and multivariate analysis of fixed-effects model, evinced that decreased AAPR also had adverse effect on disease-free survival (DFS) , progression-free survival (PFS) , and cancer-specific survival (CSS) . Admittedly, heterogeneity and publication bias existed, but stratification of univariate meta-analytic results, as well as adjusted meta-analytic results via trim and fill method, all showed that AAPR still significantly correlated with poor OS despite of confounding factors.In total, 18 studies involving 25 cohorts with 7019 cases were incorporated. Pooled results originated from both univariate and multivariate analyses (In summary, decreased AAPR had adverse effect on prognosis in cancer patients. As an inexpensive and convenient ratio derived from liver function test, AAPR might become a promising indicator of prognosis in human cancers.The online version contains supplementary material available at 10.1186/s12885-021-07921-6. Cancer is a major public health problem worldwide and is the second leading cause of death in the United States . Accordiliver diseases, inflammation, malnutrition, and diabetes mellitus, etc.) [osteosarcoma, testicular neoplasm, prostate cancer, pancreatic cancer, breast cancer, and ovarian cancer, etc.), and its elevation was usually correlated with poor outcomes [Liver function test (LFT) is an universally used laboratory test to assess liver function in clinical work. Serving as an indicator of LFT, albumin is the most abundant protein in human plasma, and its concentration reflects the protein status of the blood and function of internal organs. Meanwhile, albumin is also a valuable biomarker of diverse diseases, including both malignant tumors and benign diseases  , 6. Alkas, etc.) . Besidesoutcomes . Interesoutcomes . Hencefooutcomes –26.However, results from these emerging findings are inconsistent. For instance, some of them evinced that elevated AAPR was associated with poor survival outcomes , 23–26, Preferred Reporting Items for Systemic Reviews and Meta-analysis (PRISMA) issued in 2009 [This meta-analysis was conducted in accordance with  in 2009 .albumin-to-alkaline phosphatase ratio in All Text OR albumin to alkaline phosphatase ratio in All Text OR AAPR in All Text” used in Cochrane Library, “ OR AAPR) OR albumin to alkaline phosphatase ratio OR Albumin/alkaline Phosphatase Ratio)” used in PubMed, TS =  used in Web of Science. The searching time without starting time updated to May 24th, 2020. During the process of full-text reading, the references of retrieved literatures were further manually browsed to find underlying literature.We systemically sought relevant literatures in 3 databases . The search strategies were “In this process, we selected the literatures based on three major criteria. First, the clinical study investigated the prognostic determinant role of AAPR regardless of human cancer type. Secondly, the survival endpoints of mentioned cancers are required to be well documented, including overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), progression-free survival (PFS) and/or cancer-specific survival (CSS). Lastly, the hazard ratios (HRs) of the study endpoints should either be original or be calculated by utilizing the data, tables or graphs provided in the literature. We discarded case reports, review articles and comment letters. In situations where multiple literature used data from the same population sources, we preferred the literature with the maximum amount of cases.Newcastle-Ottawa Scale (NOS) score was utilized to assess the included literature quality [Two authors (AL and SDW) generated a compiled table, including the following contents: 1st author, year of publication, cancer site, sample size, study duration, design approach, cutoff value of AAPR, number of cases in each group, treatment strategy, survival outcome, HR data, analytic method (univariate/multivariate), HR source and follow-up interval. If the HR was not raw, the software Engauge Digitizer 4.1 was used to read the Kaplan-Meier curve to estimate the number of deaths/recurrences/survivors. Then, HR with its 95% CI was estimated by following practical methods  created by Tierney et al. . The aut quality . During I2, and the significance was set at either or both of P < 0.1 and I2 > 50%. In case of both I2 < 50% and P ≥ 0.1, we used a fixed-effects model to compute the pooled HRs. Otherwise, the random-effects model was adopted to perform data analysis. In addition, we assessed publication bias by following Begg’s and Egger’s methods [trim and fill method to further testify the stability of pooled results, when cases of publication bias were found [P value that is less than 0.05 was deemed as significant. In this research, we followed the methodology of statistic analysis, which was also used in our previously published research [Software STATA 14 was utilized for data analysis in this research. HRs and 95% CIs were combined to evaluate the overall impact of AAPR on prognosis, including OS, DFS, PFS and CSS. If the lower limit of pooled 95% CIs was greater than 1, the decreased AAPR was considered to have an adverse effect on prognosis. Heterogeneity across included studies was examined by Chi-square test and  methods , 31. We re found . Across research .As shown in Fig. HR = 2.14, 95%CI:1.83–2.51, P ≤ 0.001) of random-effects model  [Fig. HR = 1.93, 95%CI:1.75–2.12, P ≤ 0.001) of the fixed-effects model  [Fig. Regarding OS, 17 studies involving 20 cohorts with 5921 cases by univariate analytic results and 15 studies involving 20 cohorts with 6156 cases by multivariate analytic results were collected in total. It showed that the decreased AAPR had an adverse effect on OS in patients with cancers, which is not only taken from pooled univariate analytic results , revealing that decreased AAPR also had adverse effect on DFS  by the fixed-effects model [Fig. There were a total of nine studies involving 10 cohorts with 3014 cases and six studies involving 7 cohorts with 2584 cases separately investigating the impact of AAPR on DFS via univariate and multivariate analysis. Heterogeneity existed in neither of these two pooled meta-analyses  supported that decreased AAPR also corelated with poor PFS  [Fig. I2 = 5.6%, p = 0.347; I2 = 26.4%, p = 0.244; respectively), decreased AAPR also correlated with poor CSS  [Fig. On the whole, two studies with 331 cases and two studies with 309 cases was separately used to evaluate the impact of AAPR on PFS by univariate and multivariate analysis, respectively. The pooled meta-analysis results of the fixed-effects model , which was examined by following both Begg’s and Egger’s methods. But, publication bias existed in the meta-analysis with OS via both univariate and multivariate analytic results . Upon further investigation of the adjusted meta-analysis results by following the trim and fill method, AAPR is still significantly correlated with poor OS [Fig. Publication bias did not exist in meta-analysis with DFS via either univariate or multivariate analytic results , or meta-analysis based on diagnostic research is still warranted to clarify this issue.The underlining mechanism behind AAPR becoming a prognostic indicator of human cancers should be due to the pathological properties of hypoalbuminemia and hyperphosphatasia. Indeed, the decrease of AAPR could be caused by either one or both of the two abnormalities, both of which significantly correlate with poor outcomes in human cancers. When compared with single indicator—hypoalbuminemia or hyperphosphatasia, AAPR might contribute to identifying more patients with poor prognosis, because some cases might present with normal serum albumin levels but hyperphosphatasia, or normal serum ALP levels but hypoalbuminemia. It’s well-known that both albumin and ALP are common serum biochemical indicators used during clinical work. Therefore, we inferred that AAPR can serve as a more practical and more comprehensive indicator of prognosis in human cancers. However, our meta-analysis results were based on available researches from Asian countries, the prognostic role of AAPR in cancers also needs to be assessed by further research in western countries, especially research conducted in the greater cancer community. Additionally, well-designed clinical diagnostic research based on large scale  scores for incorporated studies of this meta-analysis.