What are the 100 most cited fungal genera?

The global diversity of fungi has been estimated between 2 to 11 million species, of which only about 155 000 have been named. Most fungi are invisible to the unaided eye, but they represent a major component of biodiversity on our planet, and play essential ecological roles, supporting life as we know it. Although approximately 20 000 fungal genera are presently recognised, the ecology of most remains undetermined. Despite all this diversity, the mycological community actively researches some fungal genera more commonly than others. This poses an interesting question: why have some fungal genera impacted mycology and related fields more than others? To address this issue, we conducted a bibliometric analysis to identify the top 100 most cited fungal genera. A thorough database search of the Web of Science, Google Scholar, and PubMed was performed to establish which genera are most cited. The most cited 10 genera are Saccharomyces, Candida, Aspergillus, Fusarium, Penicillium, Trichoderma, Botrytis, Pichia, Cryptococcus and Alternaria. Case studies are presented for the 100 most cited genera with general background, notes on their ecology and economic significance and important research advances. This paper provides a historic overview of scientific research of these genera and the prospect for further research. Citation: Bhunjun CS, Chen YJ, Phukhamsakda C, Boekhout T, Groenewald JZ, McKenzie EHC, Francisco EC, Frisvad JC, Groenewald M, Hurdeal VG, Luangsa-ard J, Perrone G, Visagie CM, Bai FY, Blaszkowski J, Braun U, de Souza FA, de Queiroz MB, Dutta AK, Gonkhom D, Goto BT, Guarnaccia V, Hagen F, Houbraken J, Lachance MA, Li JJ, Luo KY, Magurno F, Mongkolsamrit S, Robert V, Roy N, Tibpromma S, Wanasinghe DN, Wang DQ, Wei DP, Zhao CL, Aiphuk W, Ajayi-Oyetunde O, Arantes TD, Araujo JC, Begerow D, Bakhshi M, Barbosa RN, Behrens FH, Bensch K, Bezerra JDP, Bilanski P, Bradley CA, Bubner B, Burgess TI, Buyck B, Cadez N, Cai L, Calaça FJS, Campbell LJ, Chaverri P, Chen YY, Chethana KWT, Coetzee B, Costa MM, Chen Q, Custódio FA, Dai YC, Damm U, de Azevedo Santiago ALCM, De Miccolis Angelini RM, Dijksterhuis J, Dissanayake AJ, Doilom M, Dong W, Alvarez-Duarte E, Fischer M, Gajanayake AJ, Gené J, Gomdola D, Gomes AAM, Hausner G, He MQ, Hou L, Iturrieta-González I, Jami F, Jankowiak R, Jayawardena RS, Kandemir H, Kiss L, Kobmoo N, Kowalski T, Landi L, Lin CG, Liu JK, Liu XB, Loizides M, Luangharn T, Maharachchikumbura SSN, Makhathini Mkhwanazi GJ, Manawasinghe IS, Marin-Felix Y, McTaggart AR, Moreau PA, Morozova OV, Mostert L, Osiewacz HD, Pem D, Phookamsak R, Pollastro S, Pordel A, Poyntner C, Phillips AJL, Phonemany M, Promputtha I, Rathnayaka AR, Rodrigues AM, Romanazzi G, Rothmann L, Salgado-Salazar C, Sandoval-Denis M, Saupe SJ, Scholler M, Scott P, Shivas RG, Silar P, Souza-Motta CM, Silva-Filho AGS, Spies CFJ, Stchigel AM, Sterflinger K, Summerbell RC, Svetasheva TY, Takamatsu S, Theelen B, Theodoro RC, Thines M, Thongklang N, Torres R, Turchetti B, van den Brule T, Wang XW, Wartchow F, Welti S, Wijesinghe SN, Wu F, Xu R, Yang ZL, Yilmaz N, Yurkov A, Zhao L, Zhao RL, Zhou N, Hyde KD, Crous PW (2024). What are the 100 most cited fungal genera? Studies in Mycology 108: 1-411. doi: 10.3114/sim.2024.108.01.

Obtainment, selection and characterization of a mutant strain of Kluyveromyces marxianus that displays improved production of 2-phenylethanol and enhanced DAHP synthase activity.

AIMS: Yeasts produce 2-phenylethanol (2-PE) from sugars via de novo synthesis; however, its synthesis is limited due to feedback inhibition on the isofunctional 3-deoxy-d-arabino-heptulosonate-7-phosphate (DAHP) synthases (Aro3p and Aro4p). This work aimed to select Kluyveromyces marxianus mutant strains with improved capacity to produce 2-PE from sugars. METHODS AND RESULTS: Kluyveromyces marxianus CCT 7735 mutant strains were selected from UV irradiation coupled with screening of p-fluoro-dl-phenylalanine (PFP) tolerant strains on culture medium without l-Phe addition. Most of them produced 2-PE titres higher than the parental strain and the Km_PFP41 mutant strain stood out for displaying the highest 2-PE specific production rate. Moreover it showed higher activity of DAHP synthase than the parental strain. We sequenced both ARO3 and ARO4 genes of Km_PFP41 mutant and identified mutations in ARO4 which caused changes in both size and conformation of the Aro4p. These changes seem to be associated with the enhanced activity of DAHP synthase and improved production of 2-PE exhibited by that mutant strain. CONCLUSIONS: The Km_PFP41 mutant strain presented improved 2-PE production via de novo synthesis and enhanced DAHP synthase activity. SIGNIFICANCE AND IMPACT OF THE STUDY: The mutant strain obtained in this work may be exploited as a yeast cell factory for high-level synthesis of 2-PE.

Establishment and cryptic transmission of Zika virus in Brazil and the Americas.

Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil. Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 December 2016) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 2016). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease. However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus.

Ferulic acid lowers body weight and visceral fat accumulation via modulation of enzymatic, hormonal and inflammatory changes in a mouse model of high-fat diet-induced obesity.

Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20-25 g (n=6-8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF-α, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses.

[Effectiveness of management of children with severe trauma in a pediatric trauma center and in an adult trauma center: A before-after study]. / Efficacité de la prise en charge des traumatismes graves de l'enfant en salle d'accueil des urgences vitales adulte ou pédiatrique : une étude avant-après.

OBJECTIVE: To compare management of injured children in an adult trauma center (TC) with competencies in pediatric trauma care (2005-2007) and in a pediatric-only trauma center (2010-2012). STUDY DESIGN: A before-after retrospective study. PATIENTS AND METHODS: Fifty-nine children between 1 and 15 years of age admitted to the adult TC (2005-2007) were compared to 56 children admitted to the pediatric TC (2010-2012). Epidemiological data, severity scores, early outcome, and care duration in trauma resuscitation before whole-body CT were collected and compared between the two periods. RESULTS: This study found no significant differences between the two periods in terms of care duration before the whole-body CT scan (28 min [18-40] vs 26.5 min [21-36], P=0.89) and early mortality (eight children [13.5%] vs ten children [17.8%], P=0.35). CONCLUSION: With no differences in early management of injured children demonstrated, this study validates the organization within our pediatric trauma center. The effectiveness of management of children between 1 and 15 years of age with severe trauma seems to be similar in the two contexts.

High genetic variability in endophytic fungi from the genus Diaporthe isolated from common bean (Phaseolus vulgaris L.) in Brazil.

AIMS: The goals of the present study were to identify, to analyse the phylogenetic relations and to evaluate the genetic variability in Diaporthe endophytic isolates from common bean. METHODS AND RESULTS: Diaporthe sp., D. infecunda and D. phaseolorum strains were identified using multilocus phylogeny (rDNA ITS region; EF1-α, ß-tubulin, and calmodulin genes). IRAP (Inter-Retrotransposon Amplified Polymorphism) and REMAP (Retrotransposon-Microsatellite Amplified Polymorphism) molecular markers reveal the existence of high genetic variability, especially among D. infecunda isolates. CONCLUSIONS: It was concluded that the multilocus phylogenetic approach was more effective than individual analysis of ITS sequences, in identifying the isolates to species level, and that IRAP and REMAP markers can be used for studying the genetic variability in the genus Diaporthe particularly at the intraspecific level. SIGNIFICANCE AND IMPACT OF THE STUDY: The combined use of molecular tools such as multilocus phylogenetic approach and molecular markers, as performed in this study, is the best way to distinguish endophytic strains of Diaporthe isolated from common bean (Phaseolus vulgaris L.).

[Severe local anesthetic intoxication in an infant undergoing circumcision]. / Intoxication grave aux anesthésiques locaux lors d'une circoncision.

Local anesthetic intoxication is an uncommon complication of regional anesthesia. We report the case of a 4-month-old infant who presented with generalized tonic-clonic seizure complicated by cardiac arrest secondary to a severe intoxication to local anesthesia. These complications were observed after a bilateral dorsal penile nerve block with lidocaine for circumcision in a non-hospital setting. This report emphasizes the potential risk of local anesthetic systemic toxicity in such circumstances and describes its treatment.

Septic arthritis: patients with or without isolated infectious agents have similar characteristics.

PURPOSE: Septic arthritis can be disabling and life-threatening, requiring prompt diagnosis and treatment. The infectious agent is not always identified in these patients. We revaluate septic arthritis cases discharged from our department, describing the affected population, causative microorganisms and antibiotic therapy used, and characterised differences between patients with and without isolated pathogenic agents. METHODS: Sixty-eight septic arthritis patients were included in this study. Diagnosis was based on clinical findings, and/or the presence of joint purulent material, and/or bacterial pathogen isolation from joint fluid/synovial membrane/blood cultures and response to antibiotics. Data analysis was performed using SPSS 20. RESULTS: Patients had a mean age of 61.1 ± 18.8 years, without sex predominance. 26.5 % had an infection ≤ 15 days before septic arthritis diagnosis. Besides previous infection, 57.4 % had ≥ 1 risk factors for septic arthritis, most commonly pharmacological immunosuppression (20.6 %), diabetes mellitus type 2 (19.1 %) and rheumatoid arthritis (17.6 %). The knee was the most often affected (54.3 %). Only 39.7 % presented fever from clinical onset until hospital admission (mean 13.4 ± 18.9 days). Leucocytosis was present in 45.6 % of patients, elevated erythrocyte sedimentation rate (ESR) in 75 % and elevated C-reactive protein (CRP) in 97.1 %. 5.9 % had articular damage attributable to septic arthritis. An infectious agent was isolated in 41.2 % of patients, with Staphylococcus aureus being the most frequent. 38.7 % of synovial fluid and 23.5 % of synovial membrane cultures were positive. Patients with an identified infectious agent have no significant differences other than more days of hospitalisation (p = 0.003) and in-hospital antibiotic treatment (p = 0.017). CONCLUSION: Synovial fluid and synovial membrane cultures more often identified pathogens compared to blood or urine cultures. Patients with and without an identified infectious agent have similar demographic, clinical, laboratory and radiographic characteristics.

Increased expression of clp genes in Lactobacillus delbrueckii UFV H2b20 exposed to acid stress and bile salts.

The ability to survive in harsh environments is an important criterion to select potential probiotics strains. The objective of this study was to identify and carry out phylogenetic and expression analysis by quantitative real-time PCR of the clpP, clpE, clpL and clpX genes in the probiotic strain Lactobacillus delbrueckii UFV H2b20 exposed to the conditions prevailing in the gastrointestinal tract (GIT). Phylogenetic trees reconstructed by Bayesian inference showed that the L. delbrueckii UFV H2b20 clpP, clpL and clpE genes and the ones from L. delbrueckii ATCC 11842 were grouped. The exposure of cells to MRS broth of pH 3.5 for 30 and 60 min resulted in an increased expression of the four genes. Exposure of the L. delbrueckii UFV H2b20 cells for 30 and 60 min to MRS broth containing 0.1% bile salts increased the expression of the clpP and clpE genes, while the expression level of the clpL and clpX genes increased only after 30 min of exposure. The involvement of the studied genes in the responses to acid stress and bile salts suggests a possible central role of these genes in the survival of L. delbrueckii UFV H2b20 during the passage through the GIT, a characteristic necessary for probiotic strains.

Carboxyl ester hydrolase from Penicillium expansum: cloning, characterization and overproduction by Penicillium griseoroseum.

AIMS: In this study, a gene that encodes a carboxylesterase (carb) in Penicillium expansum GF was cloned, sequenced and overexpressed by Penicillium griseoroseum PG63, and the enzyme was characterized. METHODS AND RESULTS: The recombinant strain, P. griseoroseum T55, obtained upon transformation using the plasmid pAN-52-1-carb, showed integration of the carb gene into at least two heterologous sites of the genome by Southern blotting. Furthermore, the recombinant strain T55 exhibited almost a fourfold increase in carboxylesterase activity compared with PG63 strain when both were cultured without inducers. Based on the secondary structure and multiple sequence alignments with carboxylesterases, cholinesterase and lipase, a three-dimensional model was obtained. The α/ß barrel topology, that is typical of esterases and lipases, was indicated for the CARB protein with Ser(213)-Glu(341)-His(456) as the putative catalytic triad. CARB preferentially hydrolysed acyl chains with eight carbon atoms, and its activity was optimal at a pH of 7·0 and a temperature of 25°C. CARB exhibited stability in alkaline pH, high activity under mesophilic conditions and stability in organic solvents. CONCLUSION: The CARB protein is potentially useful in bioremediation, food and chemical/pharmaceutical industries. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first to report the development of a recombinant strain superproducing a Penicillium sp. carboxylesterase.

Genetic diversity analysis of isolates of the fungal bean pathogen Pseudocercospora griseola from central and southern Brazil.

Planting resistant varieties is the most effective control measure against the angular leaf spot of dry beans, a fungal disease caused by Pseudocercospora griseola. However, dry bean varieties with durable resistance are not easily obtained. Knowledge about the genetic variability of the pathogen population is key for the success of dry bean breeding programs aimed at developing resistant materials, but finding suitable operationally simple and genetically accurate markers is not an easy task. The aim of this study was to assess the suitability of the ISSR-PCR technique to quantify the genetic variability of P. griseola isolates. Total DNA of 27 P. griseola isolates from Goiás, Minas Gerais, Espírito Santo, and Paraná States was extracted and amplified using specific primers for ISSR. Using cluster analysis, 27 genotypes were identified. The ISSR-PCR technique was suitable for assessing intraspecific variability of P. griseola. The ISSR-PCR marker was found to be highly sensitive to genetic variation and can aid in elucidating the genetic structure of the population of this plant pathogen as a support tool for the dry bean breeding programs.

Improved pectinase production in Penicillium griseoroseum recombinant strains.

AIMS: To obtain recombinant strains of Penicillium griseoroseum that produce high levels of pectin lyase (PL) and polygalacturonase (PG) simultaneously. METHODS AND RESULTS: A strain with high production of PL was transformed with the plasmid pAN52pgg2, containing the gene encoding PG of P. griseoroseum, under control of the gpd promoter gene from Aspergillus nidulans. Southern blot analysis demonstrated that all strain had at least one copy of pAN52pgg2 integrated into the genome. The recombinant strain P. griseoroseum T20 produced levels of PL and PG that were 266- and 27-fold greater, respectively, than the wild-type strain. Furthermore, the extracellular protein profile of recombinant T20 showed two protein bands of c. 36 and 38 kDa, associated with PL and PG, respectively. CONCLUSIONS: This recombinant strain T20 produces PL and PG using carbon sources of low costs, and an enzyme preparation that is free of cellulolytic and proteolytic activities. SIGNIFICANCE AND IMPACT OF THE STUDY: PL and PG play an important role in the degradation of pectin. Owing to their use in the juice and wines industries, there is a growing interest in the inexpensive production of these enzymes. This work describes an efficient system of protein expression and secretion using the fungus P. griseoroseum.

Mathematical modelling of negative feedback regulation by carboxyltransferase.

Acetyl-CoA carboxylase catalyses the first committed step in fatty acid synthesis in all organisms. The chemistry is accomplished in two half-reactions: activation of biotin via carboxylation by biotin carboxylase, followed by the carboxyltransferase-catalysed transfer of the carboxyl moiety from carboxybiotin to acetyl-CoA to generate malonyl-CoA. The Escherichia coli form of the carboxyltransferase subunit was recently found to regulate its own activity and expression by binding its own mRNA. By binding acetyl-CoA or the mRNA encoding its own subunits, carboxyltransferase is able to sense the metabolic state of the cell and attenuate its own translation and enzymatic activity using a negative feedback mechanism. Here, the network of these interactions is modelled mathematically with a set of non-linear differential equations. Numerical simulations of the model show that it qualitatively and quantitatively agrees with the experimental results for both inhibition of carboxyltransferase by mRNA and attenuation of translation. The modelling of the autoregulatory function of carboxyltransferase confirms that it is more than isolated interactions, but functions as a single dynamic system.

Overexpression of kermit/dGIPC is associated with lethality in Drosophila melanogaster

Insertional mutagenesis is an important tool for functional genomics in Drosophila melanogaster. The insertion site in the KG00562 mutant fly line has been mapped to the CG8709 (herein named DmLpin) locus and to the 3’ of kermit (also called dGIPC). This mutant line presents a high lethality rate resulting from a gain of function. To obtain some insight into the biological role of the mutated locus, we have characterized the mutation and its relation to the high mortality of the KG00562 fly line. In this mutant, we did not detect one of the DmLpin transcripts, namely DmLpinK, but we did detect an unusual 2.3-kb mRNA (LpinK-w). Further investigation revealed that the LpinK-w transcript results from an aberrant splicing between the untranslated first exon of DmLpinK and the mini-white marker gene. Lack of DmLpinK or LpinK-w expression does not contribute to lethality, since heterozygous KG00562/Def7860 animals presented lethality rates comparable to those of the wild type. In contrast, the overexpression of kermit was associated with lethality of the KG00562 fly line. Significantly higher levels of kermit were detected in the Malpighian tubules of KG00562/+ flies that presented higher lethality rates than wild-type or KG00562/Def7860 animals, in which the lethality was rescued. In agreement with a recently reported study, our data support the hypothesis that misexpression of kermit/dGIPC could interfere with Drosophila development, with further investigations being needed in this direction.

Overexpression of kermit/dGIPC is associated with lethality in Drosophila melanogaster.

Insertional mutagenesis is an important tool for functional genomics in Drosophila melanogaster. The insertion site in the KG00562 mutant fly line has been mapped to the CG8709 (herein named DmLpin) locus and to the 3' of kermit (also called dGIPC). This mutant line presents a high lethality rate resulting from a gain of function. To obtain some insight into the biological role of the mutated locus, we have characterized the mutation and its relation to the high mortality of the KG00562 fly line. In this mutant, we did not detect one of the DmLpin transcripts, namely DmLpinK, but we did detect an unusual 2.3-kb mRNA (LpinK-w). Further investigation revealed that the LpinK-w transcript results from an aberrant splicing between the untranslated first exon of DmLpinK and the mini-white marker gene. Lack of DmLpinK or LpinK-w expression does not contribute to lethality, since heterozygous KG00562/Def7860 animals presented lethality rates comparable to those of the wild type. In contrast, the overexpression of kermit was associated with lethality of the KG00562 fly line. Significantly higher levels of kermit were detected in the Malpighian tubules of KG00562/+ flies that presented higher lethality rates than wild-type or KG00562/Def7860 animals, in which the lethality was rescued. In agreement with a recently reported study, our data support the hypothesis that misexpression of kermit/dGIPC could interfere with Drosophila development, with further investigations being needed in this direction.

[Ultrasound-guided supraclavicular subclavian vein catheterization: a novel approach in children]. / Abord de la veine sous-clavière par voie sus-claviculaire sous échographie: une nouvelle approche en pédiatrie.

The subclavian vein (SCV) is often the preferred site for long-term central venous catheterization in children. It has many advantages over the internal jugular vein. But with the classical landmark technique for SCV catheterization the ultrasound-guidance technique is usually not suitable, because of the clavicle (a bright hyperechoic structure with an acoustic shadow beneath it). Because the SCV can easily be visualized via a supraclavicular approach, we developed a useful ultrasound-guided approach for SCV catheterization in infants and children.

La representación social de los portadores de SIDA o tuberculosis: una experiencia del cuidar en la terapia ocupacional / The social representation of the carriers of AIDS or tuberculosis: an experience of caring in occupational therapy

El presente trabajo se fundamenta en las bases teóricas de la atención en Terapia Ocupacional (TO) y en la teoría de la representación social. Desarrolladas en clientes con tuberculosis (TB) o SIDA, en un hospital universitario, evaluando visando la adherencia al tratamiento. La cuestión central de esta investigación es el carácter relacional entre el tratamiento y el portador de TB o SIDA. Así, se objetiva caracterizar como la TO puede contribuir con la adhesión al tratamiento. Algunas preguntas fueron contestadas: ¿cómo es la organización de los clientes entorno de hechos que constituyen sus medios físico y social?; ¿será que la TO puede cuidar de estas personas? ¿la TO puede facilitar la adherencia al tratamiento? La estrategia para la producción de datos fue apoyada en Talleres de Creatividad, con 12 clientes, por medio de la actividad artística. Los pacientes hablaron de los sentimientos que surgen en la relación entre el desarrollo y la convivencia con sus enfermedades. Los resultados mostraron que la TO contribuye con la disminución de comportamientos agresivos facilitando la adhesión al tratamiento. La conclusión es que la TO, favorece a que las personas, se preparen para hacer frente a las reacciones adversas, provocando la adhesión al tratamiento.

This work builds upon the theories of care in Occupational Therapy (OT) and the theory of social representation. Developed in clients with tuberculosis (TB) and AIDS in a university hospital, aiming to assess adherence to treatment. The central question of this research is the relational character between the treatment and the carrier of TB or AIDS. That objectively characterized as the OT can help with treatment adherence. Some questions were answered: How is the organization of the customers’ environment facts constituting their physical and social? Can it be that the OT can take care of these people? OT may facilitate adherence to treatment? The strategy for data production was supported in Creativity Workshops, with 12 clients, through artistic activity. Patients spoke of the feelings that arise in the relationship between development and living with their diseases. The results showed that the OT contributes with decrease of aggressive behavior by facilitating treatment compliance. The conclusion is that the OT, encourages people to prepare to cope with adverse events causing treatment adherence.