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The 20th century witnessed the dawn of the antibiotic revolution and is now facing the rising phenomenon of antibiotic resistance. In this narrative review, we aim to describe antibiotic resistance in clinical practice settings through population-based studies from different countries reporting the role of misuse of antibiotics in the development of resistance and the clinical and economic burden associated. The misuse of antibiotics was documented in the wide population as well as in hospitals and care facilities. It was mainly reported as over-use and inappropriate prescribing. Improper dosage regimens and longer treatment duration were regarded as pivotal factors related to antibiotic resistance; the emerging strategy of \"antibiotic-de-escalation\" could be the key to overcome these issues. The investigation of the self-medication attitude revealed widespread antibiotic use without following medical instructions or medical consultation. Moreover, several studies established the association of antibiotic resistance with increased risk of longer hospitalizations and mortality, highlighting the heavy clinical and economic burden of this phenomenon. In this narrative review, the widespread inappropriate use of antibiotics emerged as one of the main causes of antibiotic resistance, which negative outcomes call for the development of antibiotic stewardship programs and global surveillance networks.

Although lysyl oxidase-like 1 ( LOXL1 ) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis -acting effect on the expression levels of LOXL1 , mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1 , eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression. LOXL1 is a genetic risk factor for pseudoexfoliation syndrome of the eye but a causal variant has not been identified. Here, Pasutto et al ., find intronic LOXL1 risk variants influence transcription factor binding and alternative splicing of LOXL1 in affected tissues reducing levels of LOXL1 mRNA.

Poor medication adherence leads to worsening of clinical outcomes and increases healthcare costs, especially in the context of chronic conditions. The effects of new COVID-19 infection and the measures taken in response to the outbreak are further increasing the concerns about medication adherence. Patients with chronic diseases, many of whom are older adults, have been strongly recommended to stay at home and avoid social contacts even with family members, who often provide support for regular use of therapies. Moreover, the mobilization of health personnel to the frontline of the COVID-19 infection could limit access to healthcare services. Within the Health-DB project, the Fail-To-Refill monitoring system was designed to evaluate the lack of adherence to chronic therapies in Italian clinical practice settings. Considering the date and dose coverage of last prescription, all patients due to refill this prescription for a chronic therapy in the last month were identified, and it was verified if they had the refill. The proposed future analysis, based on the data linkage between the current administrative flows of the Italian Local Health Units involved, will be carried out on a monthly basis from the beginning of the infection, and the \"post-Covid-19\" results will be compared with \"pre-COVID-19\" results, calculated for the last three years for patients with chronic therapies. Preliminary data herein presented showed a trend of increased failed refill during the months of lockdown for lipid-lowering and biologic therapies. The pre-COVID-19 trend compared to that of post-COVID-19 in the next months will be useful to estimate the percentage of failure to refill truly related to COVID-19 and on the measures adopted. The identification of patients that do not refill their prescriptions allows healthcare professionals to put in place actions aimed to promptly correct the lack of adherence, thus reducing the associated negative outcomes.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1 . They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci. Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A , have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1 , which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10 −14 ) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci ( P < 5 × 10 −8 ). We identified association signals at 13q12 ( POMP ), 11q23.3 ( TMEM136 ), 6p21 ( AGPAT1 ), 3p24 ( RBMS3 ) and 5q23 (near SEMA6A ). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Tin Aung, Chiea-Chuen Khor and colleagues report the results of a genome-wide association study of exfoliation syndrome. They replicate a known association at LOXL1 and identify a previously unreported association at CACNA1A . Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus ( CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10 −11 ). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker ( LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR A allele = 9.87, P = 2.13 × 10 −217 ; non-Japanese: OR A allele = 0.49, P = 2.35 × 10 −31 ). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Genetic and nongenetic factors contribute to development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process frequently associated with glaucoma. To identify specific genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) using a DNA-pooling approach. Therefore, equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls were combined into separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data were analyzed and visualized with expressly developed software tools GPFrontend and GPGraphics in combination with GenePool software. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used. Of 19, 17 SNPs showing significant allele frequency difference in DNA pools were confirmed by individual genotyping. Further single genotyping at CNTNAP2 locus revealed association between PEX/PEXG for two SNPs, which was confirmed in an independent German but not the Italian cohort. Both SNPs remained significant in the combined German cohorts even after Bonferroni correction (rs2107856: P c =0.0108, rs2141388: P c =0.0072). CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells. Confirming efficiency of GWAS with DNA-pooling approach by detection of the known LOXL1 locus, our study data show evidence for association of CNTNAP2 with PEX syndrome and PEXG in German patients.

Chiea Chuen Khor, Tin Aung and colleagues report the results of a large genome-wide association study of primary angle closure glaucoma. They identify five new susceptibility loci and provide insights into disease pathogenesis. Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10 −15 ), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10 −16 ), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10 −14 ), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10 −11 ), and DPM2 – FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10 −12 ). We also confirmed significant association at three previously described loci ( P < 5 × 10 −8 for each sentinel SNP at PLEKHA7 , COL11A1 , and PCMTD1 – ST18 ) 1 , providing new insights into the biology of PACG.

Tin Aung, Mineo Ozaki, Takanori Mizoguchi, R Rand Allingham, Zheng Li, Aravind Haripriya, Satoko Nakano, Steffen Uebe, Jeffrey M Harder, Anita S Y Chan, Mei Chin Lee, Kathryn P Burdon, Yury S Astakhov, Khaled K Abu-Amero, Juan C Zenteno, Yildirim Nilgün, Tomasz Zarnowski, Mohammad Pakravan, Leen Abu Safieh, Liyun Jia, Ya Xing Wang, Susan Williams, Daniela Paoli, Patricio G Schlottmann, Lulin Huang, Kar Seng Sim, Jia Nee Foo, Masakazu Nakano, Yoko Ikeda, Rajesh S Kumar, Morio Ueno, Shin-ichi Manabe, Ken Hayashi, Shigeyasu Kazama, Ryuichi Ideta, Yosai Mori, Kazunori Miyata, Kazuhisa Sugiyama, Tomomi Higashide, Etsuo Chihara, Kenji Inoue, Satoshi Ishiko, Akitoshi Yoshida, Masahide Yanagi, Yoshiaki Kiuchi, Makoto Aihara, Tsutomu Ohashi, Toshiya Sakurai, Takako Sugimoto, Hideki Chuman, Fumihiko Matsuda, Kenji Yamashiro, Norimoto Gotoh, Masahiro Miyake, Sergei Y Astakhov, Essam A Osman, Saleh A Al-Obeidan, OhoudOwaidhah, Leyla Al-Jasim, Sami Al Shahwan, Rhys A Fogarty, Paul Leo, Yaz Yetkin, Çilingir Oguz, Mozhgan Rezaei Kanavi, Afsaneh Naderi Beni, Shahin Yazdani, Evgeny L Akopov, Kai-Yee Toh, Gareth R Howell, Andrew C Orr, Yufen Goh, Wee Yang Meah, Su Qin Peh, Ewa Kosior-Jarecka, Urszula Lukasik, Mandy Krumbiegel, Eranga N Vithana, Tien Yin Wong, Yutao Liu, Allison E Ashley Koch, Pratap Challa, Robyn M Rautenbach, David A Mackey, Alex W Hewitt, Paul Mitchell, Jie Jin Wang, Ari Ziskind, Trevor Carmichael, RangappaRamakrishnan, Kalpana Narendran, Rangaraj Venkatesh, Saravanan Vijayan, Peiquan Zhao, Xueyi Chen, Dalia Guadarrama-Vallejo, Ching Yu Cheng, Shamira A Perera, Rahat Husain, Su-Ling Ho, Ulrich-Christoph Welge-Luessen, Christian Mardin, Ursula Schloetzer-Schrehardt, Axel M Hillmer, Stefan Herms, Susanne Moebus, Markus M Nöthen, Nicole Weisschuh, Rohit Shetty, Arkasubhra Ghosh, Yik Ying Teo, Matthew A Brown, Ignacio Lischinsky, Blue Mountains Eye Study GWAS Team, Wellcome Trust Case Control Consortium 2, Jonathan G Crowston, Michae Coote, Bowen Zhao, Jinghong Sang, Nihong Zhang, Qisheng You, Vera Vysochinskaya, Panayiota Founti, Anthoula Chatzikyriakidou, Alexandros Lambropoulos, Eleftherios Anastasopoulos, Anne L Coleman, M Roy Wilson, Douglas J Rhee, Jae Hee Kang, Inna May-Bolchakova, Steffen Heegaard, Kazuhiko Mori, Wallace L M Alward, Jost B Jonas, Liang Xu, Jeffrey M Liebmann, Balram Chowbay, Elke Schaeffeler, Matthias Schwab, Fabian Lerner, Ningli Wang, Zhenglin Yang, Paolo Frezzotti, Shigeru Kinoshita, John H Fingert, Masaru Inatani, Kei Tashiro, André Reis, Deepak P Edward, Louis R Pasquale, Toshiaki Kubota, Janey L Wiggs, Francesca Pasutto, Fotis Topouzis, Michael Dubina, Jamie E Craig, Nagahisa Yoshimura, Periasamy Sundaresan, Simon W M John, Robert Ritch, Michael A Hauser & Chiea-Chuen Khor Nat.

Nat. Genet. 47, 387–392 (2015); published online 23 February 2015; corrected online 9 March 2015; corrected after print 27 April 2015 In the version of this article initially published, the name of author Afsaneh Naderi Beni was misspelled. The error has been corrected in the HTML and PDF versions of the article.