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SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce. METHODS: Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region. RESULTS: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy. CONCLUSION: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.

Humans

Subtypes of HBsAg in eastern and south-eastern Europe.

A total of 481 serum samples was collected from asymptomatic carriers of HBSAg as well as some patients with acute and chronic hepatitis, type B. The sera were obtained mainly from blood banks in the following countries: Poland, Hungary, Romania, Bulgaria, Yugoslavia, and the European part of the Soviet Union. Asymptomatic carriers of HBsAg from Poland and Hungary showed a preponderance of adw subtype over ayw subtype (Poland -80.7% adw, Hungary -72.2% adw). Carriers from the remaining countries showed the reverse situation: Bulgaria -71.5% ayw, Yugoslavia -79.0% ayw, Romania -82.8% ayw, Soviet Union -87.5% ayw. No individuals were found among these indigenous populations to have the adr or ayr subtypes but two carriers appeared to have the unusual subtype adyw.

Bulgaria

A reappraisal of abortion as a method of fertility control.

Some of the factors which led up to the passing of the British Abortion Act in 1967 (which came into effect ten years ago in April 1968) are outlined. British health advantages of the liberal and legalized abortion policy are described, as are the attitudes and opinions since passage of the act. Reference is made to the findings of the British Committee on the Working of the Abortion Act which were reported in 1974. The use of abortion as the sole method of fertility control in certain countries of Eastern Europe is discussed.

Abortion, Legal

Review of the acute admissions of 442 foreign born in closed psychiatric wards (Antwerp, 1967-1975). Comparison to native borns for age, sex, descent and diagnosis.

After reviewing the literature on transcultural psychiatry, the admissions in the closed service of the Hospital Stuyvenberg in Antwerpen were analysed for 1967-1975. Immigrants were compared with other nationals, for age, sex and psychiatric diagnosis, with regard to patients born in Belgium. For the foreigners, statistical evaluation was done for age, sex, civil status, land of origin, and jewish religion. Interesting results were obtained for paranoid syndromes in patients originating from Eastern Europe and in menopaused women.

Adolescent

Ancient DNA connects large-scale migration with the spread of Slavs.

The second half of the first millennium CE in Central and Eastern Europe was accompanied by fundamental cultural and political transformations. This period of change is commonly associated with the appearance of the Slavs, which is supported by textual evidence1,2 and coincides with the emergence of similar archaeological horizons3-6. However, so far there has been no consensus on whether this archaeological horizon spread by migration, Slavicisation or a combination of both. Genetic data remain sparse, especially owing to the widespread practice of cremation in the early phase of the Slavic settlement. Here we present genome-wide data from 555 ancient individuals, including 359 samples from Slavic contexts from as early as the seventh century CE. Our data demonstrate large-scale population movement from Eastern Europe during the sixth to eighth centuries, replacing more than 80% of the local gene pool in Eastern Germany, Poland and Croatia. Yet, we also show substantial regional heterogeneity as well as a lack of sex-biased admixture, indicating varying degrees of cultural assimilation of the autochthonous populations. Comparing archaeological and genetic evidence, we find that the change in ancestry in Eastern Germany coincided with a change in social organization, characterized by an intensification of inter- and intra-site genetic relatedness and patrilocality. On the European scale, it appears plausible that the changes in material culture and language between the sixth and eighth centuries were connected to these large-scale population movements.

DNA, Ancient

WHO global gonococcal antimicrobial surveillance programmes, 2019-22: a retrospective observational study.

BACKGROUND: Gonorrhoea and gonococcal antimicrobial resistance (AMR) remain global public health concerns, and enhanced quality-assured global surveillance of gonococcal AMR is imperative to inform management guidelines and public health policies. We aimed to describe the results of surveillance of gonococcal AMR conducted globally by WHO and discuss the actions needed to retain our ability to treat gonorrhoea. METHODS: In this retrospective observational study, we present gonococcal AMR data reported to WHO by 77 countries between Jan 1, 2019, and Dec 31, 2022. Gonococcal isolates were tested for minimum inhibitory concentrations of one to four key antimicrobials (ceftriaxone, cefixime, azithromycin, and ciprofloxacin) in each country. We used breakpoints for resistance and decreased susceptibility to antimicrobials from the European Committee on Antimicrobial Susceptibility Testing or Clinical Laboratory and Standards Institute. FINDINGS: 29 (39%) of 75 participating countries reported at least one isolate with resistance or decreased susceptibility to ceftriaxone, 28 (50%) of 56 reported resistance or decreased susceptibility to cefixime, 58 (88%) of 66 reported resistance to azithromycin, and 74 (99%) of 75 reported resistance to ciprofloxacin. Globally, azithromycin resistance is increasing, as is resistance or decreased susceptibility to ceftriaxone and cefixime, especially in the WHO Western Pacific region. Resistance to ciprofloxacin remained very high globally. Since 2017-18, the numbers of reporting countries, examined isolates, and resistant isolates have increased. However, surveillance levels remain inadequate in central America and the Caribbean, eastern Europe, and the WHO African, Eastern Mediterranean, and South-East Asia regions. INTERPRETATION: Global AMR surveillance conducted by WHO is expanding and, in selected countries, improving through standardisation and quality assurance, as well as implementation of extragenital sampling, test of cure, and whole-genome sequencing. This approach provides evidence-based data for management guidelines and public health policies. Improvements in prevention, early diagnosis, treatment of patients and their contacts, surveillance (of infection rates, AMR, treatment failures, and antimicrobial use), and antimicrobial stewardship are essential. WHO supports this work through several global action plans on AMR, new global gonorrhoea treatment recommendations, surveillance, and research. FUNDING: None.

Neisseria gonorrhoeae

The burden of male breast cancer (MBC) in the GBD Central, Eastern, and Western Europe Regions from 1990 to 2023: Results from the Global Burden of Disease Study 2023.

PURPOSE: Male breast cancer (MBC) is underrepresented in cancer statistics: this study aimed to assess the burden of MBC in Central, Eastern, and Western Europe from 1990 to 2023, using data from the Global Burden of Disease (GBD) Study 2023. METHODS: Estimates from GBD 2023 were analyzed to determine the MBC incidence, mortality, and disability-adjusted life years, their all-ages and age-standardized rates, and the 1990 through 2023 annual percent change. These estimates were compared to those for the GBD Super Regions and the Socio-Demographic Index quintile countries. RESULTS: In Central Europe, age-standardized incidence rates (ASIR) increased from 0.54 (0.40-0.76) to 1.05 (0.70-1.52), age-standardized mortality rates (ASMR) from 0.29 (0.25-0.34) to 0.40 (0.36-0.45), and age-standardized disability life-year rates (ASDR) from 7.19 (6.15-8.41) to 9.63 (8.52-11.07). In Eastern Europe, ASIR remained relatively stable, changing from 0.81 (0.56-1.19) to 0.60 (0.38-0.92), whereas ASMR decreased from 0.40 (0.33-0.49) to 0.21 (0.16-0.25) and ASDR from 10.54 (8.69-12.89) to 5.55 (4.52-6.85). In Western Europe, ASIR increased from 0.47 (0.33-0.67) to 0.88 (0.59-1.24), whereas ASMR (0.22 [0.19-0.25] vs. 0.24 [0.21-0.27]) and ASDR (5.20 [4.49-5.97] vs. 5.75 [4.96-6.66]) remained stable. CONCLUSIONS: The burden of MBC is increasing across Europe, particularly in the Central region, with huge regional differences. Population growth and variations over time impacted on the metrics. Even with a composite European scenario, the mortality-to-incidence ratio markedly declined in the three areas.

Humans

Studies on antibody to hepatitis A virus in children and adults in London.

366 specimens of serum from children and adults without liver disease were screened for antibody to hepatitis A virus (anti-HAV) by means of radioimmunoassay. 56% were born in London, 26% came to London from various parts of the United Kingdom and the remainder (18%) from various parts of the world. The prevalence of antibody was related to increasing age, ranging from 7% in children under ten years of age to 77% in adults aged 50 years or more. The prevalence of anti-HAV was significantly higher in females, in the lower socio-economic class and in those not indigenous to London. In comparison to other urban populations such as those of the United States and Western Europe, the prevalence of anti-HAV was similar in terms of the overall prevalence and age distribution. By contrast, these findings were entirely different from the countries of Eastern Europe and the Middle East where the overall prevalence was higher but the anti-HAV was equal in all ages. Thus, the findings presented indicate that hepatitis A virus infection is common in London and also shows a clear relationship to advancing age, lower socioeconomic class and the country of origin.

Adolescent

Rhinoscleroma of the lower respiratory tract.

Rhinoscleroma is a chronic granulomatous disease of the respiratory tract endemic to Eastern Europe and Central America which is being recognized with increasing frequency in other countries, including the United States. It was initially described as a lesion of the nose and upper respiratory tract, but is now known to involve the larynx, trachea and bronchi as well to cause slowly progressive asphyxia. Eleven cases of rhinoscleroma with varying degrees of involvement of the lower respiratory tract (larynx, trachea and bronchi) are presented. Present day treatment is both medical, consisting primarily of streptomycin and tetracycline, and endoscopic dilatation. Prolonged medication with careful dose control is necessary. Lower respiratory tract involvement should be considered in patients with chronic destructive granulomatous nasal pathology. This should be especially emphasized if they have an Eastern European or Central American background, or have travelled in these areas in which rhinoscleroma is endemic.

Adult

Liver Cancer Risk and Incidence Attributable to Human Immunodeficiency Virus: A Meta-Analysis and Population-Attributable Modeling Study of Over 1.2 Million Individuals.

HIV-induced immune suppression and chronic inflammation elevate the risk of cancer progression. We conducted a systematic review and meta-analysis of studies published between January 1, 1984 and October 13, 2023 to assess the association between HIV infection and liver cancer. People living with HIV (PLHIV) had a higher risk (pooled relative risk = 3.36, 95% CI: 2.72-4.15). The global PAF for HIV-attributed liver cancer was 1.43% in 2019, with a three-fold increase over the past 30 years. The Asia-Pacific region recorded the second highest new cases of HIV-attributed liver cancer in 2019, and the highest age-standardized incidence rate (ASIR) in Eastern and Southern Africa. Particularly, the ASIR of HIV-attributed liver cancer increased rapidly in Eastern Europe and Central Asia, with the highest estimated annual percentage change reaching 22.98%. PLHIV have an increased risk and incidence of liver cancer. In regions with high burden of HIV-attributed liver cancer, it is essential to integrate prevention and effective treatment for HIV, viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, and liver cancer.

Humans

[Pesticide residues in poppy seed (author's transl)].

131 samples of poppy seed imported in 1977, 1978, and 1979 were analyzed for organochlorine pesticides. The average and maximum residue levels were 0.05 and 0.42 ppm for BHC-isomers without lindane, 0.07 and 0.40 ppm for lindane, 0.016 and 0.14 ppm for total DDDT (DDT, DDD, and DDE). Other pesticides could not be detected. The residue level was much higher in the first half year of our examination. Poppy seed from Eastern Europe and Turkey showed appreciably higher contamination than imports from Western European countries.

Animals

A phospholipase A2 with anticoagulant activity. I. Isolation from Vipera berus venom and properties.

An anticoagulant protein has been isolated by DEAE cellulose chromatography and gel filtration from the venom of the Vipera berus orientale (Eastern Europe). Purification has been completed by elution on carboxymethyl cellulose with continuous gradient at constant pH. The inhibitor of coagulation was separated from the other venom enzymes, e.g. procoagulant, fibrinogenolytic, aminoesterase and amino acid oxidase activities. It was also separated from other phospholipase components which were not related to the anticoagulant property. The inhibitor appeared as a simgle polypeptidic chain protein, formed by 119 amino acid residues, with a molecular weight of 13400 and an isoelectric point of 9.2. At low saline molarity, a monomer-trimer transition of this protein was observed. Both forms had the same amino acid composition. There were six disulfide bridges without free SH groups per phospholipase molecule. Deprived of any proteolytic activity, the clotting inhibitor displayed a high phospholipase activity in the presence of calcium. Activity did no appear with EDTA buffer deprived of cation. Finely dispersed micellar suspensions were found suitable for obtaining the highest phospholipase activity. High sodium cholate concentration or methanol/chloroform/ether solvent were effective without loss of enzymatic activity. As characteristis of phospholipase A2 (EC 3.1.1.4), the degradation products identified on thin-layer chromatography induced hemolysis of human erythrocytes. The apparent Km value 1.25 - 10(-3) M was determined on phosphatidylcholine isolated from ovolecithin. This purified berus inhibitor would be of value for investigating the involvement of phospholipids in the clotting mechanism.

Amino Acids

Kepone--hazard evaluation.

Kepone is a persistent chlorinated hydrocarbon pesticide which is no longer manufactured in the U.S.A., its uses having been cancelled on April 11, 1977; previous food uses included control of the banana root borer, and non-food uses included control of tobacco wireworm, ants, and cockroaches. An adduct of Kepone, Kelevan, is now distributed by Spiess and Sohn, Chemische Fabrik, Germany, with an as yet unknown manufacturer, for control of the Colorado potato beetle in Eastern Europe and Ireland, and for control of the banana root borer in the cameroons, Caribbean, and South America. Kepone is acutely toxic and induces cumulative and delayed toxicity, neurotoxicity, and reproductive impairment, in a wide range of species including birds, rodents and humans; it is also carcinogenic in rodents. Extensive environmental dispersion, with major evidence of aquatic toxicity has been demonstrated following its recent manufacture in Hopewell, Virginia, U.S.A.

Animals