West Nile virus infections in Hungary: Epidemiological update and phylogenetic analysis of the Hungarian virus strains between 2015 and 2022.

Following the introduction of the West Nile virus (WNV) into Hungary in 2004, it has shortly become one of the most important human arbovirus infections, with a gradually increasing number of cases. The study aimed to summarize the current epidemiological situation in Hungary and sequence the WNV PCR-positive clinical specimens and virus isolates by next-generation whole genome sequencing (NGS) to obtain a detailed phylogenetic analysis of the circulating virus strains. Whole blood and urine samples from confirmed WNV-infected patients and WNV isolates were investigated by reverse transcription PCR assays. Genome sequencing was carried out by Sanger-method, followed by NGS on the Illumina MiSeq platform. Altogether 499 human infections were diagnosed between 2004 and 2022. A particularly remarkable increase in human WNV infections was observed in 2018, while the number of reported cases significantly decreased during the COVID-19 pandemic. Between 2015 and 2022, 15 WNV isolates, and 10 PCR-positive clinical specimens were investigated by NGS. Phylogenetic analysis revealed that the major European WNV lineage 2 clades, namely the Eastern European (or Russian) and the Central European (or Hungarian) clades, are presented in Hungary. Strains of the Balkan and other European clusters within the Central European clade are co-circulating in the country, following a characteristic geographical distribution. In Hungary, the presence and co-circulation of multiple lineage 2 WNV strains could be identified in the last few years. Therefore, in light of the 2018 WNV outbreak, sequence-based typing of the currently circulating strains could highly support outbreak investigations.

Double Heterozygosity for Rare Deleterious Variants in the BRCA1 and BRCA2 Genes in a Hungarian Patient with Breast Cancer.

Hereditary breast cancer is most commonly attributed to germline BRCA1 and BRCA2 gene variants. The vast majority of BRCA1 and BRCA2 mutation carriers are single heterozygotes, and double heterozygosity (DH) is a very rare finding. Here, we describe the case of a BRCA1/BRCA2 double heterozygous female proband diagnosed with breast cancer. Genetic testing for hereditary breast and ovarian cancer revealed two pathogenic variants in the BRCA1 (c.5095C>T, p.(Arg1699Trp)) and in BRCA2 genes (c.658_659delGT, p.(Val220Ilefs*4)) in heterozygous form. None of the variants were founder Jewish mutations; to our knowledge, these rare deleterious variants have not been previously described in DH patients in the literature. The patient had triple-negative unilateral breast cancer at the age of 36 and 44 years. Based on family studies, the BRCA1 variant was maternally inherited.

Specialist laboratory networks as preparedness and response tool - the Emerging Viral Diseases-Expert Laboratory Network and the Chikungunya outbreak, Thailand, 2019.

We illustrate the potential for specialist laboratory networks to be used as preparedness and response tool through rapid collection and sharing of data. Here, the Emerging Viral Diseases-Expert Laboratory Network (EVD-LabNet) and a laboratory assessment of chikungunya virus (CHIKV) in returning European travellers related to an ongoing outbreak in Thailand was used for this purpose. EVD-LabNet rapidly collected data on laboratory requests, diagnosed CHIKV imported cases and sequences generated, and shared among its members and with the European Centre for Disease Prevention and Control. Data across the network showed an increase in CHIKV imported cases during 1 October 2018-30 April 2019 vs the same period in 2018 (172 vs 50), particularly an increase in cases known to be related to travel to Thailand (72 vs 1). Moreover, EVD-LabNet showed that strains were imported from Thailand that cluster with strains of the ECSA-IOL E1 A226 variant emerging in Pakistan in 2016 and involved in the 2017 outbreaks in Italy. CHIKV diagnostic requests increased by 23.6% between the two periods. The impact of using EVD-LabNet or similar networks as preparedness and response tool could be improved by standardisation of the collection, quality and mining of data in routine laboratory management systems.

The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development.

Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligation-dependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.

Imported Zika virus infections in Hungary between 2016 and 2018.

Zika virus is a mosquito-borne flavivirus with significant public health concern due to its association with neurological symptoms and intrauterine malformations. Although it is endemic in tropical and subtropical areas, sexual transmission raises the possibility of autochthonous spreading elsewhere. We describe the first laboratory diagnosed imported Zika-infections of Hungary, to highlight the challenges of microbiological identification of the pathogen, caused by serological cross-reactivity and short viremia. Serological examination was carried out using indirect immunofluorescent assay and enzyme-linked immunosorbent assay. Plaque-reduction neutralization test was used for verification purposes. A wide range of clinical specimens: serum, whole-blood, urine, saliva, and semen were analyzed by molecular methods, and sequencing was applied in case of PCR positive results to identify the virus strain. Zika-infected patients with previous vaccination against flaviviruses or possible flavivirus infection in the past showed high serological cross-reactivity, and even cross-neutralizing antibodies were observed. Zika virus RNA could be detected in urine specimen in case of two patients, and in EDTA-anticoagulated whole-blood sample of one patient. The detected strains belong to the Asian lineage of the virus. We presume that serological investigation of imported Zika virus could be altered by infections, vaccination of endemic flaviviruses in Hungary and vice versa.

Extraordinary increase in West Nile virus cases and first confirmed human Usutu virus infection in Hungary, 2018.

BackgroundDuring the 2018 WNV transmission season, similarly to other endemic areas in Europe, a large number of human West Nile virus (WNV) infections were reported in Hungary.AimsWe summarise the epidemiological and laboratory findings of the 2018 transmission season and expand experiences in flavivirus differential diagnostics.MethodsEvery patient with clinical suspicion of acute WNV infection was in parallel tested for WNV, tick-borne encephalitis virus and Usutu virus (USUV) by serological methods. Sera, whole blood and urine samples were also tested for the presence of viral nucleic acid.ResultsUntil the end of December 2018, 215 locally acquired and 10 imported human WNV infections were notified in Hungary. All reported cases were symptomatic; most of them exhibited neurological symptoms. In a large proportion of tested individuals, whole blood was the most appropriate sample type for viral nucleic acid detection, but because whole blood samples were not always available, testing of urine samples also extended diagnostic possibilities. In addition, the first human USUV infection was confirmed in 2018 in a patient with aseptic meningitis. Serological cross-reactions with WNV in different serological assays were experienced, but subsequent molecular biological testing and sequence analysis identified Europe lineage 2 USUV infection.ConclusionCareful interpretation and simultaneous application of different laboratory methods are necessary to avoid misdiagnosis of human USUV cases. Expansion of the laboratory-confirmed case definition criteria for detection of viral RNA in any clinical specimens to include urine samples could increase diagnostic sensitivity.

[Detection of West Nile virus in human samples: follow-up studies during the 2015 seasonal period]. / A nyugat-nílusi vírus kimutatása humán betegmintákból: nyomon követéses vizsgálatok a 2015. évi szezonális idoszakban.

INTRODUCTION: West Nile virus, a mosquito-borne viral zoonosis is responsible for human infections in Hungary. Laboratory diagnosis is based on serological tests, however the application of molecular methods has been appreciated. AIM: The aim of the study was to investigate blood, cerebrospinal-fluid and urine samples of acutely ill patients and to follow-up PCR positive cases to ascertain the length of virus excretion. METHOD: Clinical specimens were examined by indirect-immunofluorescent, haemagglutination-inhibition, two PCR tests and Sanger-sequencing. Virus isolation in case of two patients was successful. RESULTS: A follow-up study could be carried out in case of 5 patients. Viral nucleic acid was detectable in urine even for several weeks after symptom onset and viral RNA was present at higher concentration compared with other samples. CONCLUSIONS: PCR analysis of urine could provide useful epidemiological and diagnostic information. Therefore, it is recommended to collect urine samples in order to supplement the serological diagnosis. Orv Hetil. 2017; 158(20): 791-796.

Detection and sequencing of West Nile virus RNA from human urine and serum samples during the 2014 seasonal period.

West Nile virus, a widely distributed mosquito-borne flavivirus, is responsible for numerous animal and human infections in Europe, Africa and the Americas. In Hungary, the average number of human infections falls between 10 and 20 cases each year. The severity of clinically manifesting infections varies widely from the milder form of West Nile fever to West Nile neuroinvasive disease (WNND). In routine laboratory diagnosis of human West Nile virus infections, serological methods are mainly applied due to the limited duration of viremia. However, recent studies suggest that detection of West Nile virus RNA in urine samples may be useful as a molecular diagnostic test for these infections. The Hungarian National Reference Laboratory for Viral Zoonoses serologically confirmed eleven acute human infections during the 2014 seasonal period. In three patients with neurological symptoms, viral RNA was detected from both urine and serum specimens, albeit for a longer period and in higher copy numbers with urine. Phylogenetic analysis of the NS3 genomic region of three strains and the complete genome of one selected strain demonstrated that all three patients had lineage-2 West Nile virus infections. Our findings reaffirm the utility of viral RNA detection in urine as a molecular diagnostic procedure for diagnosis of West Nile virus infections.

Musculoskeletal ultrasonography in routine rheumatology practice: data from Central and Eastern European countries.

The main aim was to gain structured insight into the use of musculoskeletal ultrasonography (MSUS) in routine rheumatology practices in Central and Eastern European (CEE) countries. In a cross-sectional, observational, international, multicenter survey, a questionnaire was sent to investigational sites in CEE countries. Data on all subsequent routine MSUS examinations, site characteristics, MSUS equipment, and investigators were collected over 6 months or up to 100 examinations per center. A total of 95 physicians at 44 sites in 9 countries provided information on a total of 2810 MSUS examinations. The most frequent diagnoses were rheumatoid arthritis (RA) and spondyloarthritis (34.8 and 14.9 % of cases, respectively). Mean number of joints examined was 6.8. MSUS was most frequently performed for diagnostic purposes (58 %), particularly in patients with undifferentiated arthritis, suspected soft tissue disorders, or osteoarthritis (73.0-85.3 %). In RA patients, 56.3 % of examinations were conducted to monitor disease activity. Nearly all investigations (99 %) had clinical implications, while the results of 78.6 % of examinations (51.6-99.0 %) were deemed useful for patient education. This first standardized multicountry survey performed in CEEs provided a structured documentation of the routine MSUS use in participating countries. The majority of MSUS examinations were performed for diagnostic purposes, whereas one-third was conducted to monitor disease activity in RA. A majority of examinations had an impact on clinical decision making and were also found to be useful for patient education.

Diagnosis of Dengue Virus Infections Imported to Hungary and Phylogenetic Analysis of Virus Isolates.

BACKGROUND: Dengue virus is one of the most important arbovirus infections of public health concern. Between 2017 and June 2022, 75 imported dengue infections were confirmed by laboratory diagnostic methods in Hungary. Our study aimed to isolate the imported Dengue strains and characterize them by whole-genome sequencing. METHODS: Laboratory diagnosis of imported infections was carried out using both serological and molecular methods. Virus isolation was attempted on Vero E6 cell lines. An in-house amplicon-based whole-genome sequencing method was applied for the detailed molecular characterization of the isolated virus strains. RESULTS: From 75 confirmed Dengue infected patients, 68 samples were used for virus isolation. Isolation and whole-genome sequencing were successful in the case of eleven specimens. Isolated strains belonged to Dengue-1,-2,-3 serotypes. DISCUSSION: The isolated strains corresponded to the circulating genotypes of the visited geographic area, and some of the genotypes were linked with more severe DENV cases in the literature. We found that multiple factors, including viral load, specimen type, and patient antibody status, influence the isolation efficacy. CONCLUSIONS: Analysis of imported DENV strains can help estimate the outcomes of a possible local DENV transmission in Hungary, a threat from the near future.

Impact of adalimumab in patients with active non-infectious intermediate, posterior, and panuveitis in real-life clinical practice: HOPE study.

BACKGROUND/AIM: This study evaluated real-life adalimumab impact in patients with active non-infectious intermediate, posterior, or panuveitis (NIIPPU). METHODS: Adults with active NIIPPU received adalimumab in this prospective, observational study (06/2017-04/2020). Patients were evaluated at baseline (V0) and four follow-up visits over 12 months (V1-V4). PRIMARY ENDPOINT: proportion of patients achieving quiescence (anterior chamber (AC) cells grade and vitreous haze (VH) grade≤0.5+ in both eyes, no new active chorioretinal lesions) at any follow-up visit. Secondary endpoints: proportion of patients achieving quiescence at each visit; proportion of patients maintaining response; and proportion of patients with flares. Workability, visual function, healthcare resource utilisation, and safety were evaluated. RESULTS: Full analysis set included 149 patients. Quiescence at any follow-up visit was achieved by 129/141 (91%) patients. Quiescence at individual visits was achieved by 99/145 (68%), 110/142 (77%), 102/131 (78%), and 99/128 (77%) patients at V1-V4, respectively. Number of patients in corticosteroid-free quiescence increased from 51/147 (35%; V1) to 67/128 (52%; V4; p<0.05). Proportion of patients with maintained response increased from 89/141 (63%; V2) to 92/121 (76%; V4; p<0.05) and proportion of patients with flare decreased from 25/145 (17%; V1) to 13/128 (10%; V4; p=0.092). Workability and visual function improved throughout the study. Proportion of patients with medical visits for uveitis decreased from 132/149 (89%; V0) to 27/127 (21%; V4). No new safety signals were observed. CONCLUSION: These results demonstrated adalimumab effectiveness in improving quality of life while reducing economic burden of active NIIPPU.

Attempt to increase the transparency of fourth hurdle implementation in Central-Eastern European middle income countries: publication of the critical appraisal methodology.

BACKGROUND: In middle income countries the number of trained health technology assessment specialists is limited and the public budget for health technology assessment is considerably lower compared to developed countries. These countries therefore must develop their own solutions to improve the quality and efficiency of health technology assessment implementation in reimbursement decisions. Our study aimed to develop a scientifically rigorous and detailed appraisal checklist for economic evaluations of pharmaceuticals in the single health technology assessment process. METHODS: The research design entailed a review of economic evaluations, submitted for reimbursement of pharmaceuticals, by two independent academic reviewers to identify the most common methodological problems. Fifty economic evaluations submitted in 2007-2008, randomly selected by the Health Technology Assessment Office served as data sources. The new checklist was developed by an iterative working process: first by assessing ten economic evaluations, then improving the checklist by generating new question items, then employing the improved checklist to assess the next ten economic evaluations. After appraising 25 documents, the reviewers reconciled their opinions and improved the checklist with the researchers of the Health Technology Assessment Office during an expert panel discussion. The reviewers scrutinized the second 25 economic evaluations, after which the expert panel finalized the checklist with consensus. RESULTS: The final checklist consists of 91 yes or no questions in 11 main topics concerning comparator selection, efficacy, effectiveness, costs, sensitivity analysis, methodological approach, transparency, and interpretation of results. The new checklist is based on current Hungarian evaluation practice. As the published checklist will be part of the official single health technology assessment process of pharmaceuticals, submitters will be able to assure the quality of their economic evaluation. CONCLUSIONS: The transparent critical appraisal method should improve the consistency of pharmaceutical reimbursement decisions and facilitate the utilization of economic evaluations in other fields of health care decision-making in other Central-Eastern European countries.

Value of Remission in Patients with Rheumatoid Arthritis: A Targeted Review.

The treat-to-target strategy, which defines clinical remission as the primary therapeutic goal for rheumatoid arthritis (RA), is a widely recommended treatment approach in clinical guidelines. Achieving remission has been associated with improved clinical outcomes, quality of life, and productivity. These benefits are likely to translate to reduced economic burden in terms of lower healthcare costs and resource utilization. As such, a literature review was conducted to better understand the economic value of remission. Despite the large heterogeneity found in RA-related economic outcomes across studies, patients in remission consistently had lower direct medical and indirect costs, less healthcare resource utilization, and greater productivity compared to those without remission. Remission was associated with 19-52% savings in direct medical costs and 37-75% savings in indirect costs. The economic value of remission should thus be considered in economic analyses of RA therapies to inform treatment and reimbursement decisions.

Case Report: Expressive Speech Disorder in a Family as a Hallmark of 7q31 Deletion Involving the FOXP2 Gene.

Pathogenic variants of FOXP2 gene were identified first as a monogenic cause of childhood apraxia of speech (CAS), a complex disease that is associated with an impairment of the precision and consistency of movements underlying speech, due to deficits in speech motor planning and programming. FOXP2 variants are heterogenous; single nucleotide variants and small insertions/deletions, intragenic and large-scale deletions, as well as disruptions by structural chromosomal aberrations and uniparental disomy of chromosome 7 are the most common types of mutations. FOXP2-related speech and language disorders can be classified as "FOXP2-only," wherein intragenic mutations result in haploinsufficiency of the FOXP2 gene, or "FOXP2-plus" generated by structural genomic variants (i.e., translocation, microdeletion, etc.) and having more likely developmental and behavioral disturbances adjacent to speech and language impairment. The additional phenotypes are usually related to the disruption/deletion of multiple genes neighboring FOXP2 in the affected chromosomal region. We report the clinical and genetic findings in a family with four affected individuals having expressive speech impairment as the dominant symptom and additional mild dysmorphic features in three. A 7.87 Mb interstitial deletion of the 7q31.1q31.31 region was revealed by whole genome diagnostic microarray analysis in the proband. The FOXP2 gene deletion was confirmed by multiplex ligation-dependent probe amplification (MLPA), and all family members were screened by this targeted method. The FOXP2 deletion was detected in the mother and two siblings of the proband using MLPA. Higher resolution microarray was performed in all the affected individuals to refine the extent and breakpoints of the 7q31 deletion and to exclude other pathogenic copy number variants. To the best of our knowledge, there are only two family-studies reported to date with interstitial 7q31 deletion and showing the core phenotype of FOXP2 haploinsufficiency. Our study may contribute to a better understanding of the behavioral phenotype of FOXP2 disruptions and aid in the identification of such patients. We illustrate the importance of a targeted MLPA analysis suitable for the detection of FOXP2 deletion in selected cases with a specific phenotype of expressive speech disorder. The "phenotype first" and targeted diagnostic strategy can improve the diagnostic yield of speech disorders in the routine clinical practice.

Imported tropical arbovirus infections in Hungary between 2016 and 2020 / Magyarországra behurcolt trópusi arbovírusfertozések 2016 és 2020 között.

Összefoglaló. Bevezetés: A Dengue-, Zika- és Chikungunya-vírus-fertozések a trópusokról importált leggyakoribb arbovírusfertozések. Földrajzi elterjedésük átfedo, közös vektoraik és hasonló tüneteik miatt szerológiai és molekuláris módszerek együttes alkalmazásán alapuló mikrobiológiai vizsgálatokkal különíthetok el megbízhatóan. Célkituzés: Munkánk célja a 2016 és 2020 között endémiás területen járt, tünetes és tünetmentes utazók vizsgálata volt, minden esetben mindhárom vírusfertozés irányában. A diagnosztikus tesztek során az alvadásgátolt teljes vér és vizelet bevonásával vizsgáltuk a vírus-RNS kimutathatóságának esélyét a különbözo mintatípusokból. Módszer: Savópárminták szerológiai analízise során a Dengue-, Zika- és Chikungunya-vírus-specifikus ellenanyagválasz alakulását vizsgáltuk ELISA-módszerrel. Reaktív eredmények esetében a szerológiai keresztreakciók kizárására immunfluoreszcens és ELISA-technikán alapuló további vizsgálatokat végeztünk a hazai és az utazás során érintett területeken eloforduló flavi- és alphavirusok irányában. Vérsavó-, alvadásgátolt teljes vér és vizeletmintákból reverztranszkripciót követo valós ideju polimeráz-láncreakcióval vírus-RNS-kimutatást végeztünk. Eredmények: Az 1037 vizsgált utazó közül 133 esetben kaptunk reaktív szerológiai és/vagy molekuláris eredményt. Az alvadásgátolt teljes vér mintából sikerült a legnagyobb arányban vírusnukleinsavat kimutatni mind a Dengue- és Zika-, mind a Chikungunya-vírus esetében. Megbeszélés: Endémiás területrol hazatért utazók vizsgálatát a tünetek hasonlósága miatt mindhárom vírusfertozés irányában együttesen indokolt elvégezni. A flavi- és alphavirusokra jellemzo nagyfokú szerológiai keresztreaktivitás miatt a nukleinsav-kimutatás javíthatja a mikrobiológiai diagnosztika pontosságát. Következtetés: A három vírus mikrobiológiai diagnosztikáját segíti a korai mintavétel és a molekuláris vizsgálatok kiterjesztése további mintatípusokra: alvadásgátolt teljes vér és vizelet. A behurcolt vírusfertozések azonosítása fokozott jelentoségu, mert az Európában is jelen lévo vektorszúnyogfajok felvetik az autochton átvitel lehetoségét. Orv Hetil. 2021; 162(50): 2000-2009. INTRODUCTION: Dengue-, Zika- and Chikungunya infections are among the most frequently imported tropical arbovirus infections. Due to their shared endemic regions, vectors and similar clinical symptoms, differential diagnosis is based on serological and molecular analysis. OBJECTIVE: The aim of our study was to identify the imported arbovirus infections of travellers between 2016 and 2020. Furthermore, to improve the diagnostic sensitivity, anticoagulated whole blood and urine samples were involved in molecular diagnosis. METHOD: Virus-specific antibody kinetics was tested in paired sera of patients by ELISA method. In case of reactive results, further serological analysis was performed using immunofluorescence assays and/or ELISA tests to exclude serological cross-reactions caused by other members of the flavi- and alphaviruses. Detection of viral RNA was attempted from serum, anticoagulated whole blood and urine specimens using reverse transcription and real-time polymerase chain reaction. RESULTS: Out of the tested 1037 travellers, reactive serological and/or molecular results were obtained in 133 cases. Anticoagulated whole blood proved to be the most suitable specimen for viral RNA detection of the three viruses. DISCUSSION: Parallel testing of Dengue-, Zika- and Chikungunya infections is recommended, as symptom-based differential diagnosis is challenging. Due to the characteristic serological cross-reactivity of flavi- and alphaviruses, microbiological diagnosis relies on both serological and molecular tests. CONCLUSION: Involving anticoagulated whole blood and urine samples into molecular analysis and early sample collection improve the sensitivity of microbiological diagnostics. Identification of imported tropical arbovirus infections is of high importance as the presence of vector mosquitos in Europe raises the possibility of autochthon transmission. Orv Hetil. 2021; 162(50): 2000-2009.

Patient satisfaction, preferences, expectations, characteristics, and impact of suboptimal control of rheumatoid arthritis: A subgroup analysis of Japanese patients from a large international cohort study (SENSE).

OBJECTIVE: To evaluate treatment satisfaction, disease outcomes, and perspectives of patients with poorly controlled rheumatoid arthritis (RA) treated with conventional synthetic, targeted synthetic, or biologic disease-modifying antirheumatic drugs (DMARDs), we conducted a subgroup (post hoc) analysis of Japanese patients participating in the SENSE study. METHODS: Data for Japanese patients (n/N = 118/1629) from the global, multicenter, cross-sectional, observational SENSE study were analyzed. The primary endpoint was the global satisfaction subscore assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Other patient-reported outcomes included self-reported RA medication adherence and Work Productivity and Activity Impairment-RA. Patient perspectives included patients' expectations and preference of pharmacologic treatment. RESULTS: Median (range) age and RA disease duration were 67.0 (18.0-87.0) years and 8 (0.0-54) years, respectively; 81.4% of patients were female. Mean (SD) TSQM global satisfaction subscore was 56.8 (17.5), and only 5.9% of patients reported good satisfaction with treatment (TSQM global ≥80). Mean (SD) self-reported treatment adherence using VAS was high (93.5% [13.8%]). Mean (SD) total work productivity impairment was 45.6% (32.0%); presenteeism contributed toward more total work productivity impairment (43.9% [30.4%]) than absenteeism (8.3% [24.4%]). Patients expected improvement in all parameters from their treatment, especially improvement in joint symptoms. Most patients (80.7%) preferred oral medication and 18.7% preferred monotherapy. Patient acceptability of potentially manageable side effects was high (7.5%-34.0%). Although most patients (81.3%) found combination therapy acceptable, 43.2% were receiving DMARD monotherapy. CONCLUSION: Although most Japanese patients with RA with moderate-to-high disease activity were dissatisfied with their current DMARD treatment, high treatment adherence, high acceptability of combination therapy, high acceptability of manageable potential side effects, and preference for oral medication were reported. Data support the development of a more individualized and patient-centric approach for RA treatment.

Systemic Screening for 22q11.2 Copy Number Variations in Hungarian Pediatric and Adult Patients With Congenital Heart Diseases Identified Rare Pathogenic Patterns in the Region.

Congenital heart defects (CHD) are the most common developmental abnormalities, affecting approximately 0.9% of livebirths. Genetic factors, including copy number variations (CNVs), play an important role in their development. The most common CNVs are found on chromosome 22q11.2. The genomic instability of this region, caused by the eight low copy repeats (LCR A-H), may result in several recurrent and/or rare microdeletions and duplications, including the most common, ∼3 Mb large LCR A-D deletion (classical 22q.11.2 deletion syndrome). We aimed to screen 22q11.2 CNVs in a large Hungarian pediatric and adult CHD cohort, regardless of the type of their CHDs. All the enrolled participants were cardiologically diagnosed with non-syndromic CHDs. A combination of multiplex ligation-dependent probe amplification (MLPA), chromosomal microarray analysis and droplet digital PCR methods were used to comprehensively assess the detected 22q11.2 CNVs in 212 CHD-patients. Additionally, capillary sequencing was performed to detect variants in the TBX1 gene, a cardinal gene located in 22q11.2. Pathogenic CNVs were detected in 5.2% (11/212), VUS in 0.9% and benign CNVs in 1.8% of the overall CHD cohort. In patients with tetralogy of Fallot the rate of pathogenic CNVs was 17% (5/30). Fifty-four percent of all CNVs were typical proximal deletions (LCR A-D). However, nested (LCR A-B) and central deletions (LCR C-D), proximal (LCR A-D) and distal duplications (LCR D-E, LCR D-H, LCR E-H, LCR F-H) and rare combinations of deletions and duplications were also identified. Segregation analysis detected familial occurrence in 18% (2/11) of the pathogenic variants. Based on in-depth clinical information, a detailed phenotype-genotype comparison was performed. No pathogenic variant was identified in the TBX1 gene. Our findings confirmed the previously described large phenotypic diversity in the 22q11.2 CNVs. MLPA proved to be a highly efficient genetic screening method for our CHD-cohort. Our results highlight the necessity for large-scale genetic screening of CHD-patients and the importance of early genetic diagnosis in their clinical management.

Treatment Satisfaction, Patient Preferences, and the Impact of Suboptimal Disease Control in a Large International Rheumatoid Arthritis Cohort: SENSE Study.

BACKGROUND: Patients' needs and perspectives are important determinants of treatment success in rheumatoid arthritis (RA). Assessing patients' perspectives can help identify unmet needs and enhance the understanding of treatment benefits. OBJECTIVE: The SENSE study assessed the impact of inadequate response to disease-modifying antirheumatic drugs (DMARDs) on treatment satisfaction, disease outcomes, and patient perspectives related to RA disease management. METHODS: SENSE was a noninterventional, cross-sectional study conducted in 18 countries across Europe, Asia, and South America. Adult patients with poorly controlled RA of moderate/high disease activity were eligible. Patient satisfaction was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM v1.4). Treatment adherence, healthcare resource utilization (HRU), quality of life (QoL), work ability, digital health literacy (DHL), patient preference information, and treatment strategy were also assessed. RESULTS: A total of 1624 patients were included in the study: most were female (84.2%) and middle-aged, and mean disease duration was 10.5 years. Mean TSQM global satisfaction subscore was 60.9, with only 13.5% of patients reporting good treatment satisfaction (TSQM global ≥80). The strongest predictor of good treatment satisfaction was treatment with advanced therapies. Most patients (87.4%) reported good treatment adherence. In general, patients had impaired QoL and work ability, high HRU, and 67.4% had poor DHL. Leading treatment expectations were "general improvement of arthritis" and "less joint pain". Most patients preferred oral RA medications (60.7%) and rapid (≤1 week) onset of action (71.1%). "Increased risk for malignancies" and "increased risk for cardiovascular disease" were the least acceptable side effects. Despite suboptimal control, advanced therapies were only used in a minority of patients, and DMARD switches were planned for only half of the patients. CONCLUSION: Suboptimal disease control negatively impacts treatment satisfaction, work ability, QoL, and HRU. Data collected on patient perspectives may inform shared decision-making and optimize treat-to-target strategies for improving patient outcomes in RA.

22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum.

Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low-set ears, and intellectual disability seem to be the most consistent features. Familial reoccurrence is extremely rarely reported. Here, we report 2 siblings with a 22q13.3qter duplication detected by array CGH; their mother is a carrier of a pericentric inversion in chromosome 22. Their relatively mild phenotype and identical chromosomal breakpoints as well as duplication size are unique. This is the first case described so far.

Upadacitinib versus placebo or adalimumab with background methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate: a subgroup analysis of a phase III randomized controlled trial in Central and Eastern European patients.

BACKGROUND: In the randomized, phase III, global SELECT-COMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients. METHODS: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted. RESULTS: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks. CONCLUSION: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks.