Search

Objective: To confirm a previously reported association of TRPV1 rs8065080 with the risk of transformation from episodic (EM) to chronic migraine (CM) and to extend knowledge about the role of other TRPV1 single nucleotide polymorphisms (SNPs), we first investigated the impact of three TRPV1 SNPs (rs8065080, rs222747 and rs222749) on the risk of migraine chronification in a case-control study. A systematic review and meta-analysis were then conducted to summarize the accumulated findings., Methods: Genotyping of the selected TRPV1 SNPs was performed using TaqMan real-time PCR in 167 EM and 182 CM participants. Crude and adjusted odds ratios with associated 95% confidence intervals were calculated in the log-additive, dominant, and recessive genetic models. A comprehensive literature search was performed in PubMed, Web of Knowledge, Cochrane Library, and OpenGrey until February 2024., Results: In our case-control study, no association was found between TRPV1 SNPs and the risk of migraine chronification, both in the unadjusted logistic regression models and after adjustment for confounding clinical variables. The results of the meta-analysis with a total of 241 participants with EM and 223 with CM confirmed no association between TRPV1 SNPs and the risk of migraine chronification in any of the genetic models tested., Conclusion: The results of the present case-control study and meta-analysis exclude a major role of TRPV1 rs8065080, rs222747, and rs222749 as risk factors for migraine chronification. However, further research is needed to investigate the gene-gene and gene-environment interactions of TRPV1 SNPs on the risk of transformation from episodic to chronic migraine., (© 2024. The Author(s).)

Purpose: Inconclusive and limited results have been reported on the clinical utility of CYP2C19 genotyping in stroke/TIA patients of non-East Asian ancestries. We herein performed an updated systematic review and meta-analysis to quantitatively estimate the association of CYP2C19 loss-of function (LOF) status with efficacy and safety of clopidogrel-based antiplatelet therapy in non-East Asian patients affected by stroke or TIA., Methods: A comprehensive search was performed up to July 2023 using PubMed, Web of Knowledge, and Cochrane Library databases. The clinical outcomes investigated were stroke, composite vascular events and bleeding. Pooled estimates were calculated as risk ratios (RR) with 95% CI using the Mantel- Haenszel random-effects model. The quality of evidence was assessed using the GRADEpro tool., Results: A total number of 1673 stroke/TIA patients from 8 non-East Asian studies, published between 2014 and 2022, were included in the systematic review. Clopidogrel-treated carriers of CYP2C19 LOF alleles were found at increased risk of stroke compared to non-carriers (RR: 1.68, 95%CI: 1.04-2.71, P = 0.03). However, no significant association was observed with the risk of composite vascular events (RR: 1.15, 95%CI: 0.58-2.28, P = 0.69) or bleeding (RR: 0.84, 95%CI: 0.38-1.86, P = 0.67). Similarly, European ancestry patients carrying CYP2C19 LOF alleles displayed a higher risk of stroke (RR: 2.69 (1.11-6.51, P = 0.03), but not of composite vascular events or bleeding., Conclusion: The present updated meta-analysis provides moderate quality evidence of association between CYP2C19 LOF alleles and an increased risk of stroke in non-East Asian patients with stroke/TIA after receiving clopidogrel therapy. Further large pharmacogenetic studies are still warranted to corroborate these findings., (© 2023. The Author(s).)

Background: In order to clarify the role of the maternal apolipoprotein E (ApoE) genotype and the risk of recurrent pregnancy loss (RPL), we herein performed an updated systematic review and meta-analysis to reevaluate the evidence on this association., Methods: A comprehensive literature search was performed on PubMed, Web of Knowledge and the Cochrane library up to September 2022. Methodological study quality was assessed using the Newcastle-Ottawa Scale and the credibility of significant pooled odds ratios (ORs) was estimated by the false positive report probability and the Bayesian false discovery probability., Results: Twelve studies published from 2009 to 2022 fulfilled the inclusion criteria. In the overall analysis, the ε4 allele was found to confer an increased risk of RPL compared to the ε3 allele (OR 1.60, 95% CI 1.00-2.55, p = 0.049) and women carrying the ApoE ε4 allele displayed a higher risk of RPL compared with those carrying the ε2 and ε3 alleles (OR 1.75, 95% CI 1.06-2.87, p = 0.028). Subgroup analysis based on subjects' ethnicity revealed that these associations were restricted to the Asian population (ε4 allele vs. ε3 allele, OR 5.93, 95% CI 1.79-19.61, p = 0.004; ε4 allele carriers vs. carriers of ε2 and ε3 alleles, OR 8.42, 95% CI 1.47-48.12, p = 0.017). None of the associations detected were found to be noteworthy under false positive report probability or Bayesian false discovery probability at a prior probability of 0.001., Conclusions: This updated meta-analysis highlights an association between maternal ApoE genotype and RPL risk in Asians, but not in Caucasians. Further case-control studies are warranted in women of Asian ancestry to exclude the possibility of false-positive findings., (© 2022 John Wiley & Sons Ltd.)

The aim of this systematic review and network meta-analysis is to evaluate the comparative effectiveness of N95, surgical/medical and non-medical facemasks as personal protective equipment against respiratory virus infection. The study incorporated 35 published and unpublished randomized controlled trials and observational studies investigating specific mask effectiveness against influenza virus, SARS-CoV, MERS-CoV and SARS-CoV-2. We searched PubMed, Google Scholar and medRxiv databases for studies published up to 5 February 2021 (PROSPERO registration: CRD42020214729). The primary outcome of interest was the rate of respiratory viral infection. The quality of evidence was estimated using the GRADE approach. High compliance to mask-wearing conferred a significantly better protection (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.23-0.82) than low compliance. N95 or equivalent masks were the most effective in providing protection against coronavirus infections (OR, 0.30; CI, 0.20-0.44) consistently across subgroup analyses of causative viruses and clinical settings. Evidence supporting the use of medical or surgical masks against influenza or coronavirus infections (SARS, MERS and COVID-19) was weak. Our study confirmed that the use of facemasks provides protection against respiratory viral infections in general; however, the effectiveness may vary according to the type of facemask used. Our findings encourage the use of N95 respirators or their equivalents (e.g., P2) for best personal protection in healthcare settings until more evidence on surgical and medical masks is accrued. This study highlights a substantial lack of evidence on the comparative effectiveness of mask types in community settings., (© 2022 John Wiley & Sons Ltd.)

Background and Purpose: Erenumab (ERE) is the first anticalcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. A proportion of patients do not adequately respond to ERE., Methods: Prospective multicenter study involving 110 migraine patients starting ERE 70 mg monthly. Baseline socio-demographics and migraine characteristics, including mean monthly migraine days (MMDs), migraine-related burden (MIDAS [Migraine Disability Assessment scale] and Headache Impact Test-6), and use of abortive medications, during 3 months before and after ERE start were collected. Real-time polymerase chain reaction was used to determine polymorphic variants of calcitonin receptor-like receptor and receptor activity-modifying protein-1 genes. Logistic regression models were used to identify independent predictors for 50% responder patients (50-RESP) and 75% responder patients (75-RESP)., Results: At month 3, MMDs decreased from 17.2 to 9.2 (p < 0.0001), 59/110 (53.6%) patients were 50-RESP, and 30/110 (27.3%) were 75-RESP. Age at migraine onset (odds ratio [OR] [95% confidence interval (95% CI)]: 1.062 [1.008-1.120], p = 0.024), number of failed preventive medications (0.753 [0.600-0.946], p = 0.015), and MIDAS score (1.011 [1.002-1.020], p = 0.017) were associated with 75-RESP. Among the genetic variants investigated, RAMP1 rs7590387 was found associated with a lower probability of being 75-RESP (per G allele OR [95% CI]: 0.53 [0.29-0.99], p = 0.048]), but this association did not survive adjustment for confounding clinical variables (per G allele, 0.55 [0.28-1.10], p = 0.09])., Conclusions: In this real-word study, treatment with ERE significantly reduced MMDs. The number of failed preventive medications, migraine burden, and age at migraine onset predicted response to ERE. Larger studies are required to confirm a possible role of RAMP1 rs7590387 as genetic predictor of ERE efficacy., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: It is controversial whether there is efficacy or safety benefit of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in advanced EGFR-mutated non-small cell lung cancer (NSCLC) compared to standard chemotherapy. We aim to assess the efficacy and safety of EGFR-TKIs compared to other chemotherapeutics in EGFR-mutated NSCLC., Materials and Methods: Up to April 27th, 2020, PubMed, Embase, Medline, Scopus, Cochrane library, and ClinicalTrials.gov were searched for articles or trials meeting the inclusion criteria. After filtering, 230 eligible studies were initially identified. Data extraction followed PRISMA and included outcomes were progression-free survival (PFS), overall survival (OS), and severe adverse events (SAEs). Direct and indirect meta-analyses were generated in the context of log-linear mixed-effects models, with fixed effects for each relative comparison and random effects for each study., Results: The results showed that EGFR-TKI therapy had improved PFS with a hazard ratio (HR) of 0.40 (95% CI: 0.36-0.44, p<0.001) compared to standard chemotherapy. Nevertheless, the EGFR-TKIs showed no benefit on OS (HR: 0.96, 95% CI: 0.83-1.10, p=0.556). In the analysis of adverse events, EGFR-TKIs had fewer SAEs than standard chemotherapy (HR: 0.29, 95% CI: 0.26-0.33, p<0.001)., Conclusions: Our systemic review indicates that EGFR-TKI therapy has improved PFS, and reduced SAEs compared to standard chemotherapy in advanced EGFR-mutated NSCLC.

Normal tissue radiosensitivity is thought to be influenced by an individual's genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2-3 subcutaneous fibrosis and/or grade 2-3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance ( p < 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G > C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82-2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51-14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06-3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence.

Background: A plethora of studies have attempted to identify genetic determinants of disease susceptibility and treatment response of patients with cluster headache (CH), but results are often conflicting, and no comprehensive overview with a quantitative summary of the evidence in this field is available., Methods: A systematic search of relevant publications was performed without any language restrictions on PubMed, Web of Knowledge, Cochrane Library, and OpenGrey, up to December 2020. A standardized data extraction form was used to collect relevant data from each included study. Meta-analyses were conducted for gene polymorphisms investigated in at least two studies and the Bayesian false discovery probability (BFDP) test was applied to the pooled odds ratios (ORs) to assess the credibility of the observed associations., Results: Among the 27 articles identified by the systematic review, 17 studies evaluating 12 single nucleotide polymorphisms (SNPs) were included in the quantitative data analysis. The pooled results showed no significant association with CH risk of 10 SNPs, including five SNPs of HCRTR2 (rs2653349, rs2653342, rs3122156, rs10498801, and rs3800539), two SNPs of ADH4 (rs1800759 and rs1126671), CLOCK rs1801260, and two SNPs (rs1006417 and ADCYAP1R1 rs12668955) previously identified by a genome-wide association study (GWAS). Conversely, the pooled results revealed the association of the HCRTR2 rs9357855 A allele with a higher risk of CH (A vs. G, OR: 1.33, 95% CI: 1.04-1.72, p = 0.026), and of GNB3 rs5443 with a higher response rate of patients with CH to triptan drugs (CT+TT vs. CC, OR: 1.96, 95% CI: 1.04-3.72, p = 0.038). However, assuming a prior probability of 0.001, the respective BFDP values being higher than 0.8 (BFDP rs9357855  = 0.998; BFDP rs5443  = 0.998) revealed lack of noteworthy results., Conclusions: Well-designed GWASs and large replication studies are still needed to identify reliable genetic variants of disease susceptibility and treatment response of patients with CH., (© 2021 American Headache Society.)

The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2021 Elsevier Inc. All rights reserved.)

ACT's low levels of Plasmodium parasitemia clearance are worrisome since it is the last treatment option against P. falciparum. This scenario has led to investigations of compounds with different mechanisms of action for malaria treatment. Natural compounds like ursolic acid (UA) and betulinic acid (BA), distinguished by their activity against numerous microorganisms, including P. falciparum, have become relevant. This study evaluated the antiplasmodial activity of imidazole derivatives of UA and BA against P. falciparum in vitro. Eight molecules were obtained by semisynthesis and tested against P. falciparum strains (NF54 and CQ-resistant 106/cand isolated in Porto Velho, Brazil); 2a and 2b showed activity against NF54 and 106/cand strains with IC 50  < 10 µM. They presented high selectivity indexes (SI > 25) and showed synergism when combined with artemisinin. 2b inhibited the parasite's ring and schizont forms regardless of when the treatment began. In silico analysis presented a tight bind of 2b in the topoisomerase II-DNA complex. This study demonstrates the importance of natural derivate compounds as new candidates for malarial treatment with new mechanisms of action. Semisynthesis led to new triterpenes that are active against P. falciparum and may represent new alternatives for malaria drug development., (© 2021 John Wiley & Sons Ltd.)

The World Health Organization assigns international nonproprietary names (INN), also known as common names, to compounds upon request from drug developers. Structures of INNs are publicly available and represent a source, albeit underused, to understand trends in drug research and development. Here, we explain how a common drug name is composed and analyze chemical entities from 2000 to 2021. In the analysis, we describe some changes that intertwine chemical structure, newer therapeutic targets (e.g., kinases), including a significant increase in the use of fluorine and of heterocycles, and some other evolutionary modifications, such as the progressive increase in molecular weight. Alongside these, small signs of change can be spotted, such as the rise in spirocyclic scaffolds and small rings and the emergence of unconventional structural moieties that might forecast the future to come.

Purpose: To assess efficacy and safety of trastuzumab biosimilars in comparison to the reference drug through a systematic review and meta-analysis of randomized controlled trials (RCTs)., Methods: A comprehensive search was conducted using PubMed, Web of Science, Cochrane library, Open Grey and ClinicalTrials.gov databases. Dichotomous data for efficacy and safety outcomes were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs). Meta-analysis was performed with the Mantel-Haenszel method using Revman 5.3 software., Results: Eight phase III RCTs including a total of 3913 patients with HER2 + breast cancer were identified that met the inclusion criteria. The pooled results for the comparison of trastuzumab biosimilars to the reference drug showed no differences of objective response rate (ORR) (RR 1.05, 95% CI 0.98-1.12, P = 0.20) or overall survival (RR 0.82, 95% CI 0.61-1.09, P = 0.17) in the intention-to-treat population, as well as no difference of ORR (RR 1.03, 95% CI 0.97-1.10, P = 0.30) in the per-protocol population. Similarly, no significant difference was detected in any type of adverse event reported in at least three RCTs, including any serious treatment-emergent adverse effects (RR 0.97, 95% CI 0.76-1.25, P = 0.83), heart failure (RR 1.47, 95% CI 0.69-3.14, P = 0.32), neutropenia (RR 1.05, 95% CI 0.96-1.15, P = 0.26), and infusion-related reaction (RR 1.10, 95% CI 0.89-1.36, P = 0.38)., Conclusion: This meta-analysis provides compelling evidence of clinical comparability between trastuzumab biosimilars and the originator product in terms of both efficacy and safety for the treatment of HER2 + breast cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases.The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.

This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.

Eosinophilic esophagitis (EoE) is a relatively new condition described as an allergic-mediated disease of the esophagus. Clinically, it is characterized by dysphagia, food impaction, and reflux-like symptoms. Multiple genome-wide association studies (GWAS) have been conducted to identify genetic loci associated with EoE. The integration of numerous studies investigating the genetic polymorphisms in EoE and the Mendelian diseases associated with EoE are discussed to provide insights into the genetic risk of EoE, notably focusing on CCL26 and CAPN14 . We focus on the genetic loci investigated thus far, and their classification according to whether the function near the loci is known. The pathophysiology of EoE is described by separately presenting the known function of each cell and molecule, with the major contributors being eosinophils, Th2 cells, thymic stromal lymphopoietin (TSLP), transforming growth factor (TGF)-β1, and interleukin (IL)-13. This review aims to provide detailed descriptions of the genetics and the comprehensive pathophysiology of EoE.

Since 1977, the World Health Organization publishes a list of essential medicines, i.e., those that satisfy the priority health care needs of the population and are selected with regard to disease prevalence and public health relevance, evidence of clinical efficacy, and safety, as well as comparative costs and cost-effectiveness. The Essential Medicines List (EML) is an invaluable tool for all countries to select those medicines that have an excellent risk/benefit ratio and that are reputed to be of pivotal importance to health. In the present perspective, we describe the chemical composition and the main features of the small molecules that are included in the EML, spanning from their origin, to their stereochemistry and measure of drug-likeness. Most and foremost, we wish to disseminate the importance of the EML, which can be both a helpful teaching tool in an ever-expanding world of medicines and an inspiration for those involved in pharmaceutical R&D.

Contrasting results exist on the association between CTLA-4 rs231775 and acute rejection in kidney transplant recipients. We herein conducted an updated systematic review with meta-analysis and trial sequential analysis (TSA) to clarify this relationship and to establish whether the current evidence is sufficient to draw firm conclusions. In addition, noteworthiness of significant pooled odds ratios (ORs) was estimated by false positive report probability (FPRP). A comprehensive search was performed through PubMed, Web of Knowledge, Cochrane Library and Open Grey up to October 2019. Fifteen independent cohorts, including a total of 5,401 kidney transplant recipients, were identified through the systematic review. Overall, no association was detected with the allelic (OR 1.07, 95% CI 0.88-1.30, P = 0.49), dominant (OR 0.94, 95% CI 0.73-1.22, P = 0.66) or the recessive (OR 1.18, 95% CI 0.97-1.43, P = 0.096) model of CTLA-4 rs231775. In each genetic model, the cumulative Z-curve in TSA crossed the futility boundary and entered the futility area. In addition, none of the significant genetic comparisons detected in the subsequent and sensitivity analyses or in previously reported meta-analyses were found to be noteworthy by FPRP. In conclusion, this study provides strong evidence that CTLA-4 rs231775 is not a clinically-relevant genetic risk determinant of acute rejection after renal transplantation.

(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus disease 2019 (COVID-19), has been controversial. However, a meta-analysis on the efficacy of steroids in treating these coronavirus infections is lacking. (2) Purpose: We assessed a methodological criticism on the quality of previous published meta-analyses and the risk of misleading conclusions with important therapeutic consequences. We also examined the evidence of the efficacy of corticosteroids in reducing mortality in SARS, MERS and COVID-19. (3) Methods: PubMed, MEDLINE, Embase, and Web of Science were used to identify studies published until 25 April 2020, that reported associations between steroid use and mortality in treating SARS/MERS/COVID-19. Two investigators screened and extracted data independently. Searches were restricted to studies on humans, and articles that did not report the exact number of patients in each group or data on mortality were excluded. We calculated odds ratios (ORs) or hazard ratios (HRs) under the fixed- and random-effect model. (4) Results: Eight articles (4051 patients) were eligible for inclusion. Among these selected studies, 3416 patients were diagnosed with SARS, 360 patients with MERS, and 275 with COVID-19; 60.3% patients were administered steroids. The meta-analyses including all studies showed no differences overall in terms of mortality (OR 1.152, 95% CI 0.631-2.101 in the random effects model, p = 0.645). However, this conclusion might be biased, because, in some studies, the patients in the steroid group had more severe symptoms than those in the control group. In contrast, when the meta-analysis was performed restricting only to studies that used appropriate adjustment (e.g., time, disease severity), there was a significant difference between the two groups (HR 0.378, 95% CI 0.221-0.646 in the random effects model, p < 0.0001). Although there was no difference in mortality when steroids were used in severe cases, there was a difference among the group with more underlying diseases (OR 3.133, 95% CI 1.670-5.877, p < 0.001). (5) Conclusions: To our knowledge, this study is the first comprehensive systematic review and meta-analysis providing the most accurate evidence on the effect of steroids in coronavirus infections. If not contraindicated, and in the absence of side effects, the use of steroids should be considered in coronavirus infection including COVID-19.

In the present study we systematically re-analyzed results from meta-analyses and genome-wide association studies (GWASs) to assess the credibility of genetic associations with acute rejection risk in renal transplantation. A comprehensive literature search was performed on PubMed, Web of Knowledge, Cochrane library, and Open Grey up to July 2019. Methodological quality of systematic meta-analyses was assessed by the AMSTAR tool. Credibility of genetic associations was assessed by employing the Venice criteria and two Bayesian statistical approaches, the false positive report probability (FPRP) and the Bayesian false discovery probability (BFDP). Sixteen systematic meta-analyses, with a moderate-high quality score (median AMSTAR score: 9, range: 6-11) and 1 GWAS fulfilled the inclusion criteria. Overall, our systematic re-analysis has identified 9 polymorphic variants in 8 genes (ACE, CD28, CTLA-4, CYP3A5, IFNG, TNF-α, PTPRO and CCDC67) as potential risk factors for acute renal graft rejection. At the pre-specified prior probability of 0.001, the 2 SNPs identified by the GWAS (rs7976329 and rs10765602) showed no evidence of noteworthiness under FPRP or BFDP, indicating the possibility of false-positive associations. After applying the Venice criteria in combination with FPRP and BFDP to results from systematic meta-analyses, TT/AT vs AA of IFNG +874 T/A reached moderate epidemiological credibility, while weak evidence of association was found for all the other genetic comparisons. Well-designed GWASs and large replication studies with updated meta-analyses are still needed to identify reliable genetic predictors of acute renal graft rejection., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The relationship between the ataxia-telangiectasia mutated (ATM) rs1801516 gene polymorphism and risk of radiation-induced late skin side effects remains a highly debated issue. In the present study, we assessed the role of ATM rs1801516 as risk factor for radiation-induced fibrosis and telangiectasia, using the LENT-SOMA scoring scale in 285 breast cancer patients who received radiotherapy after breast conserving surgery. A systematic review with meta-analysis and trial sequential analysis (TSA) was then conducted to assess reliability of the accumulated evidence in breast cancer patients. In our cohort study, no association was found between ATM rs1801516 and grade ≥ 2 telangiectasia (GA+AA vs GG, HRadjusted: 0.699; 95%CI: 0.273-1.792, P = 0.459) or grade ≥ 2 fibrosis (GA+AA vs GG, HRadjusted: 1.175; 95%CI: 0.641-2.154, P = 0.604). Twelve independent cohorts of breast cancer patients were identified through the systematic review, of which 11 and 9 cohorts focused respectively on the association with radiation-induced fibrosis and radiation-induced telangiectasia. Pooled analyses of 10 (n = 2928 patients) and 12 (n = 2783) cohorts revealed, respectively, no association of ATM rs1801516 with radiation-induced telangiectasia (OR: 1.14; 95%CI: 0.88-1.48, P = 0.316) and a significant correlation with radiation-induced fibrosis (OR: 1.23; 95%CI: 1.00-1.51, P = 0.049), which however did not remain significant after TSA adjustment (TSA-adjusted 95%CI: 0.85-1.78). These results do not support an impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer, nevertheless further large studies are still required for conclusive evidences., Competing Interests: The authors have declared that no competing interests exist.

Background: A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Results: Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14-1.93, p = 0.003 and HR: 1.90, 95% CI: 1.43-2.54, p < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. Conclusions: The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.

The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of coadministered boosters, and discover compounds where deuterium is the basis for the mechanism of action. Nevertheless, designing, synthesizing, and developing a successful deuterated drug is far from straightforward, and the translation from concept to practice is often unpredictable. This Perspective provides an overview of the recent developments of deuteration, with a focus on deuterated clinical candidates, and highlights both opportunities and challenges of this strategy.

A large meta-analysis of genome-wide association studies has recently identified a number of risk loci for migraine without aura (MwoA). In this study, we tested the hypothesis that a genetic risk score based on single-nucleotide polymorphisms (SNPs), previously reported to be associated with MwoA at genome-wide significance, may influence headache response to triptans in patients with migraine without aura. Genotyping of rs9349379, rs2078371, rs6478241, rs11172113, rs1024905, and rs6724624 was conducted with a real-time PCR allelic discrimination assay in 172 MwoA patients, of whom 36.6% were inconsistent responders to triptans. Each genetic risk score model was constructed as an unweighted score, calculated by adding the number of risk alleles for MwoA across each SNP at selected loci. The association with headache response to triptans was evaluated by logistic regression analysis adjusted for triptan, and the P values were corrected for the false discovery rate. The genetic risk score including susceptibility risk alleles at TRPM8 rs6724624 and FGF6 rs1024905 was found to be inversely associated with risk of inconsistent response to triptans (OR, 0.62; 95%CI, 0.43-0.89; false discovery rate q value, 0.045). In addition, adding this genetic risk score to the triptan-adjusted logistic regression model significantly improved (P = .037) the discrimination accuracy, from 0.57 (95%CI, 0.50-0.65) to 0.64 (95%CI, 0.57-0.72). A modest but significant effect on risk of inconsistent response to triptans was identified for a genetic risk score model composed of 2 known risk alleles for MwoA, suggesting its potential utility in predicting headache response to triptan therapy., (© 2018, The American College of Clinical Pharmacology.)

We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose of review Medication-overuse headache is a secondary chronic headache disorder, evolving from an episodic primary headache type, caused by the frequent and excessive use of headache symptomatic drugs. While gene polymorphisms have been deeply investigated as susceptibility factors for migraine, little attention has been paid to medication-overuse headache genetics. In the present study we conducted a systematic review to identify, appraise and summarize the current findings of gene polymorphism association studies in medication-overuse headache. Methods A comprehensive literature search was conducted on PubMed and Web of Knowledge databases of primary studies that met the diagnostic criteria for medication-overuse headache according to the temporally-relevant Classification of Headache Disorder of the International Headache Society. Results A total of 17 candidate gene association studies focusing on medication-overuse headache were finally included in the qualitative review. Among these, 12 studies investigated the role of common gene polymorphisms as risk factors for medication-overuse headache susceptibility, six studies focused on the relationship with clinical features of medication-overuse headache patients, and four studies evaluated their role as determinants of clinical outcomes in medication-overuse headache patients. Conclusion Results of single studies show a potential role of polymorphic variants of the dopaminergic gene system or of other genes related to drug-dependence pathways as susceptibility factors for disease or as determinants of monthly drug consumption, respectively. In this systematic review, we summarize the findings of gene polymorphism association studies in medication-overuse headache and discuss the methodological issues that need to be addressed in the design of future studies.

Contrasting results have been reported on the role of rs628031 and rs683369 polymorphisms of SLC22A1 and rs776746 of CYP3A5 on imatinib treatment response in patients with chronic myeloid leukemia (CML). In the present study, we conducted a systematic review and meta-analysis of published studies to estimate the impact of the above-mentioned gene variants on major molecular response (MMR) or complete cytogenetic response (CCyR) in imatinib-treated CML patients. We performed a comprehensive search through PubMed, Web of Knowledge, and Cochrane databases up to September 2017. The pooled analyses showed association between carriers of SLC22A1 rs628031A allele (GA + AA vs GG, OR: 0.58, 95% CI: 0.38-0.88, P = 0.011) or rs683369G allele (CG + GG vs CC, OR: 0.64, 95% CI: 0.42-0.96, P = 0.032) and a lower MMR rate. The combined analyses also revealed a correlation between the dominant (GG + AG vs AA, OR: 2.43, 95%CI: 1.12-5.27, P = 0.024) or the allelic model (G vs A, OR: 1.72, 95% CI: 1.09-2.72, P = 0.020) of CYP3A5 rs776746 with higher CCyR rates. The subsequent sensitivity analysis confirmed the statistical significance of CYP3A5 rs776746 among Asian CML patients (dominant model OR: 3.90; 95%CI: 2.47-6.14, P < 0.001; allelic model OR: 2.08; 95% CI: 1.47-2.95, P < 0.001). In conclusion, the present meta-analysis supports the association of SLC22A1 and CYP3A5 genotypes with clinical imatinib response rates of CML patients, nevertheless further large studies, particularly in Caucasians, are still warranted to provide conclusive evidences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: TCF7L2 rs7903146 C>T polymorphism is associated with diabetes in the general population but its independent impact on cardiovascular disease is debated. On this basis, we investigated its association with major adverse cardiac events (MACE) in a single-center cohort of non-diabetic kidney transplant recipients (KTRs)., Methods: Patients with pretransplant diabetes were excluded and patients who developed post-transplant diabetes were censored at time of diagnosis., Results: rs7903146 C>T polymorphism appeared to modulate the risk of MACE: 5-year prevalence was 0.8% in CC patients, 7.2% in CT patients and 9.7% in TT patients (P<.001). TCF7L2 rs7903146 was an independent predictor of MACE in a multivariate Cox regression model (for each T allele, HR: 2.99, 95%CI: 1.62-5.52, P<.001), together with history of cardiac ischemic events (HR: 8.69, 95%CI: 3.57-21.16, P<.001), DGF (HR: 2.42, 95%CI: 0.98-5.95, P=.056) and HLA-mismatches (for each mismatch: HR: 1.55, 95%CI: 1.00-2.43, P=.053). Introduction of rs7903146 C>T polymorphism into a model based on these clinical variables significantly increased predictive power for MACE (P=.003)., Conclusions: TCF7L2 rs7903146 T allele may be strongly and independently associated with MACE in non-diabetic KTRs. These findings suggest the possibility of employing this SNP to more accurately stratify cardiological risk in KTRs., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Inconclusive results have been reported in studies investigating the association between the brain-derived neurotrophic factor (BDNF) rs6265 polymorphism and migraine. In the present study, we conducted a systematic review and meta-analysis on the published data in order to quantitatively estimate the relationship between rs6265 and migraine susceptibility. A comprehensive search was performed through PubMed, Web of Knowledge, and Cochrane databases up to October 2016. The pooled odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated to estimate the strength of the association with rs6265 under an additive, dominant, or recessive model of inheritance. A total of five studies including 1,442 cases and 1,880 controls were identified for the meta-analysis. The pooled data showed an increased risk of migraine for the allelic (OR: 1.17, 95% CI: 1.03-1.34, p  = 0.014) or the dominant model of rs6265 (OR: 1.22, 95% CI: 1.05-1.41, p  = 0.011). Statistical significance of rs6265 was lost when one single study was excluded from the analysis (dominant OR: 1.17, 95% CI: 1.00-1.38, p  = 0.054; allelic OR: 1.14, 95% CI: 0.99-1.31, p  = 0.067), suggesting lack of robustness of pooled estimates. When stratified by migraine type, a similar trend of association was detected with both MA and MO, but a statistically significant association of rs6265 was reached only with the MA subtype in the dominant model (OR: 1.22, 95% CI: 1.00-1.47, p  = 0.047). The present meta-analysis supports that BDNF rs6265 may act as a genetic susceptibility factor for migraine. Nevertheless, large-scale studies are required to confirm our findings and to assess potential modifiers of the relationship between rs6265 and migraine.

Purpose: This study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis., Materials and Methods: DNMT1 rs2228611, DNMT3A rs1550117, DNMT3A rs7581217, and DNMT3B rs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC)., Results: Kaplan-Meier curves showed significant differences among DNMT1 rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealed DNMT1 rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). Adding DNMT1 rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710)., Conclusion: DNMT1 rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.

Introduction: Despite the growing interest in circulating cell-free DNA (cfDNA), no conclusive evidence exists on the value of quantitative analysis of cfDNA for the prediction of lung cancer survival. We performed a systematic review and meta-analysis of primary studies to estimate the impact of higher baseline cfDNA levels on survival outcomes of patients with lung cancer., Methods: A comprehensive search was performed using the PubMed, Web of Knowledge, and Cochrane databases up to March 2016. The methodologic quality of identified studies was assessed by the Newcastle-Ottawa scale. Potential sources of heterogeneity were investigated via subgroup and sensitivity analyses, while publication bias was evaluated by funnel plot and Egger's test., Results: Among the 17 studies identified, 16 studies (n = 1723 patients) and 5 studies (n = 640) were included in the meta-analysis of overall survival (OS) and progression-free survival (PFS), respectively. Despite the fact that the association with PFS did not reach statistical significance (hazard ratio 1.12% [95% confidence interval 0.91-1.37), the pooled analysis for OS showed evidence of an increased risk of death in patients with higher baseline cfDNA levels (hazard ratio 1.76 [95% confidence interval 1.38-2.25]; p < 0.001). Further subgroup and sensitivity analyses confirmed this relationship, although significant between-study heterogeneity was still detected in most comparisons. The Egger's test revealed no statistical evidence of publication bias in the results., Conclusion: Our findings support the clinical validity of quantitative analysis of cfDNA for the prediction of lung cancer survival. Nevertheless, the establishment of a robust standardized method for determination of optimal cutoff thresholds is required to define the clinical relevance of cfDNA quantification for lung cancer management., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Several genetic polymorphisms modulate the risk of posttransplant diabetes mellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined., Methods: Genetic analysis was performed in 464 kidney transplantation recipients to evaluate whether transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism is associated with the risk of PTDM and a meta-analysis of similar studies including our results was performed (total kidney transplantation recipients, n = 3105). A predictive model of PTDM was built on the basis of this polymorphism and clinical parameters., Results: In our cohort, 163 patients possessed the CC genotype of rs7903146 (35.1%), 237 were CT (51.1%), and 64 were TT (13.8%): their 2 years PTDM incidence was, respectively, 7.8%, 11.9%, and 22.7%. At multivariate analysis, age (per year; hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.005-1.054; P = 0.017), body mass index (25.0-29.9 vs <25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; ≥30 vs <25.0; HR, 5.70; 95% CI, 2.77-11.74; P < 0.0001), TCF7L2 rs7903146 (per each T allele; HR, 1.81; 95% CI, 1.26-2.59; P = 0.001) and previous transplants (HR, 2.80; 95% CI, 1.39-5.64; P = 0.004) emerged as independent predictive factors for PTDM.Meta-analysis of present and 5 previous studies showed higher risk of PTDM in carriers of rs7903146 TT genotype (odds ratio, 1.95; 95% CI, 1.39-2.74; P < 0.0001) and absence of heterogeneity among studies (I = 0%).Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM., Conclusions: In renal transplant patients, TCF7L2 rs7903146 is strongly and independently associated with PTDM and might hold the potential to identify patients at risk for this complication.

Aim: To perform a systematic review and meta-analysis of studies evaluating the influence of recipient angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism on kidney function in renal transplant recipients., Materials & Methods: A comprehensive search was performed through PubMed, Web of Knowledge and Cochrane databases up to December 2014. The methodological quality of identified studies was assessed using the MINORS criteria., Results: A total of 15 studies evaluating the role of recipient ACE I/D were included in the meta-analysis. In overall analyzes and subsequent subgroup and sensitivity analyzes, no evidence emerged of an effect of ACE I/D on serum creatinine levels, creatinine clearance or glomerular filtration rate., Conclusion: Although further investigation is still needed to determine the role of donor ACE genotype, recipient ACE I/D does not play a significant role on kidney function in renal transplant patients.

Introduction: In this drug utilization study, we aimed at assessing the pattern of triptan use in Italy by means of the drug prescription databases of two local health authorities, accounting for approximately 1 million citizens., Methods: The study population included all residents aged 18 to 84 years in the Vercelli province (about 175,000 inhabitants) and in the Umbria region (about 885,000 inhabitants), who had at least one dispensation for triptans in 2012. A frequent user, who might be at risk of medication-overuse headache (MOH), was defined as a patient being dispensed at least 10 defined daily doses (DDD) of triptans every month for at least three consecutive months., Results: Triptans were used by 0.7%-1% of the population. While most patients were dispensed fewer than 60 DDDs per year, about 10% of all triptan users were classified as frequent users. In both areas, patients below the age of 29 were less likely to be frequent users while the 40- to 49-year-old population was the most affected, with no sex difference. About two-thirds of frequent users persisted in this behavior for an additional three-month period in the following six months., Conclusions: Our data indicate that approximately 10% of all triptan users in the Italian population are potentially at risk for MOH. An approach based on drug prescription databases could be useful to identify patients at risk for MOH., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Objectives/background: We herein investigated the role of polymorphisms in calcitonin gene-related peptide (CGRP)-related genes looking at the association of rs3781719 (T > C) in the calcitonin gene-related polypeptide-alpha (CALCA) gene and of rs3754701 (T > A) and rs7590387 (C > G) at the receptor activity modifying 1 (RAMP1) locus with triptan response in patients with migraine without aura (MwoA). In addition, their role was evaluated as risk factors for transformation of episodic migraine into medication overuse headache (MOH). The CGRP has a central role in the pathogenesis of migraine; however, little information is currently available concerning the role of polymorphisms in CGRP-related genes as determinants of clinical response to anti-migraine drugs or as risk factors for migraine chronification., Methods: Genotyping was conducted retrospectively by real-time polymerase chain reaction allelic discrimination assay in 219 patients with MwoA and 130 with MOH in whom migraine was the primary headache type. Gene variants association was evaluated by logistic regression analysis adjusted by confounding factors. The threshold of statistical significance was set according to the total number of polymorphisms analyzed in the current study and in previous publications arising from overlapping datasets., Results: No evidence of association was found between the three polymorphisms tested and triptan response in MwoA patients. Conversely, carriers of RAMP1 rs7590387GG displayed a lower risk of episodic migraine transformation into MOH (vs C allele carriers, odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.13-0.57, P = 0.0002; threshold of significance set at P < 0.0029). When genotype distribution for RAMP1 rs7590387 was compared between healthy controls (n = 209) and MOH patients, carriers of rs7590387GG were found at lower risk of developing MOH (OR: 0.43, 95%CI: 0.22-0.85, P = 0.011)., Conclusion: These results suggest that RAMP1 rs7590387 may have a role in the transformation of episodic migraine into MOH., (© 2015 American Headache Society.)

We aimed at validating the role of genetic variants identified by a recent genome-wide association study (GWAS) as determinants of chronic oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Eight polymorphisms (rs10486003, rs2338, rs843748, rs797519, rs4936453, rs12023000, rs17140129, and rs6924717) were genotyped in a total of 150 colorectal cancer patients of Caucasian origin receiving oxaliplatin-based chemotherapy. The severity grade of chronic OXAIPN was assessed by NCI-CTC criteria and the clinical version of the Total Neuropathy Score(©) (TNSc(©) ). None of the polymorphisms investigated was found associated with grade ≥ 2 chronic OXAIPN (NCI-CTC criteria), while a nominal association emerged for ACYP2 rs843748 when using the TNSc(©) scale (dominant model: odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10-0.75, P = 0.008). In the combined analysis of this results with data of the two previously published studies which assessed chronic OXAIPN by NCI-CTC criteria, evidence suggestive of association with chronic OXAIPN (NCI-CTC criteria) was found for ACYP2 rs843748 (dominant model: OR: 2.40, 95%CI: 1.40-5.24, P = 0.027), which, however, did not remain significant after correction for multiple testing (threshold P-value <0.00625). These findings suggest a minor role of the single nucleotide polymorphisms (SNPs) investigated as genetic determinants of chronic OXAIPN. These results also highlight the importance of replication studies with meta-analysis for validation of GWAS findings., (© 2015 Peripheral Nerve Society.)

Purpose: No information is currently available on genetic determinants of short-term response to drug withdrawal in medication overuse headache (MOH). In the present study, we aimed to evaluate the role of 14 polymorphisms in 8 candidate genes potentially relevant for drug addiction (OPRM1, DRD2, DBH, COMT, BDNF, SLC6A4, 5HT2A, and SLC1A2) as predictors for detoxification outcome of MOH patients at 2 months of follow-up., Methods: Genotyping was conducted by PCR, PCR-RFLP analysis, or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. The association between gene variants and risk of unsuccessful detoxification was evaluated by univariate and multivariate logistic regression analyses., Results: One hundred and eight MOH patients with effective drug withdrawal therapy and 65 MOH patients with unsuccessful detoxification were available for the analysis. In the multivariable logistic regression analysis, triptan overuse (odds ratio (OR) 0.271, 95% confidence interval (CI) 0.083-0.890, P = 0.031) and TT genotype carriage of DRD2 NcoI (OR 0.115, 95% CI 0.014-0.982, P = 0.048) emerged as independent predictors for unsuccessful detoxification. In addition, carriers of at least four of the six top-ranked gene variants (P < 0.10) were found at higher odds for unsuccessful detoxification than patients with ≤3 high-risk genotypes (OR 3.40, 95% CI 1.65-7.01, P = 0.001)., Conclusion: This exploratory study suggests that DRD2 NcoI may be a genetic determinant of detoxification outcome in MOH patients. Our findings also show that an approach based on the combination of multiple genetic markers could be clinically useful for identification of MOH patients at higher risk for unsuccessful detoxification.

Aim: To determine diagnostic accuracy of HLA-B*57:01 testing for prediction of abacavir-induced hypersensitivity and to quantify the clinical benefit of pretreatment screening through a meta-analytic review of published studies., Methods: A comprehensive search was performed up to June 2013. The methodological quality of relevant studies was assessed by the QUADAS-2 tool. The pooled diagnostic estimates were calculated using a random effect model., Results: Despite the presence of heterogeneity in sensitivity or specificity estimates, the pooled diagnostic odds ratio to detect abacavir-induced hypersensitivity on the basis of clinical criteria was 33.07 (95% CI: 22.33-48.97, I(2): 13.9%), while diagnostic odds ratio for detection of immunologically confirmed abacavir hypersensitivity was 1141 (95% CI: 409-3181, I(2): 0%). Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity., Conclusion: This meta-analysis demonstrates an excellent diagnostic accuracy of HLA-B*57:01 testing to detect immunologically confirmed abacavir hypersensitivity and corroborates existing recommendations.