Can risk area designation help increase vaccination coverage for Tick-Borne Encephalitis? Evidence from German claims data.

BACKGROUND AND OBJECTIVES: Although vaccine preventable, the incidence of tick-borne encephalitis (TBE) increased in Germany from 2001 to 2021 by on average 2% each year, with a peak of more than 700 TBE infections documented in 2020. TBE-risk areas, as designated by district based on incidence of human cases, expanded north- and northeastward, present in 11 of the 16 Federal States as of 2022. Using claims data from a German statutory health insurance in the Federal States of Saxony and Thuringia (AOK PLUS), we aimed to assess whether official assignment of a district to a risk area had an impact on vaccination rates in Germany. METHODS: The data covered the period from 01/01/2010 to 31/12/2018 and included information on vaccine administrations from outpatient physicians. Yearly incident vaccination rates were reported overall and by district. To investigate the association between a new designation of an incident TBE-risk area and vaccination rates, a difference-in-difference analysis was conducted. RESULTS: Overall, the incident vaccination rates increased from 6.2 to 9.5 per 1,000 person-years between 2012 and 2018, with a peak of 12.2 in 2015. While districts that had been risk-areas for the whole study period had always a higher vaccination rate compared to districts that were never categorized as risk areas, the increase between 2012 and 2018 was comparable in the two groups (3.0 and 3.2 per 1,000 person-years, respectively). In contrast, districts that were newly designated risk districts during the study period experienced a significantly larger increase in vaccination rates, going from 5.8 to 14.7 per 1,000 person-years between 2012 and 2018, with a peak of 19.6 in 2015. CONCLUSION: The results suggest that the new designation of a district as risk area has a significant positive impact on vaccination rates, which is strongest immediately after designation of risk area.

[Varicella Vaccination Coverage and Possible Factors Influencing Parental Vaccination Decisions in Munich Area 2009-2011 after Introduction of Routine Varicella Vaccination]. / Entwicklung der Varizellen-Impfraten und mögliche Einflussfaktoren auf die Impfentscheidung der Eltern im Raum München in den Jahren 2009­2011 nach Einführung der allgemeinen Varizellenimpfung.

Background and Objective: Germany introduced routine varicella vaccination for all infants aged 11-14 months in 2004; since 2009, a second dose was recommended for toddlers aged 15-23 months. In Bavaria, vaccination with combined MMRV vaccine has been routinely reimbursed since the introduction of the 2-dose vaccination schedule. We investigated varicella vaccination coverage and factors associated with parental acceptance of varicella vaccination in the area of Munich from 2009 to 2011, within the frame of the 'Bavarian Varicella Surveillance Project' (2006-2011). Method: Annual cross-sectional parent survey of random samples of 600 children aged 18-36 months in Munich on the child's vaccination status for varicella and measles, socio-demographic data and parental attitude towards varicella vaccination. Results: During 2009-2011, the first dose varicella vaccination (VV) coverage increased from 53% (2009) to 68% (2011) while the second dose VV increased from 29% (2009) to 59% (2011). First-dose measles vaccination coverage was 88-91% (2009-2011). In 2009, 51% of all vaccinated children received the combined MMRV vaccine as first dose; in 2011, 94% (p<0.001). In 2009, 27% of all parents considered varicella vaccination as superfluous. This percentage had decreased to 15% by 2011. Recommendation of varicella vaccination by the physician was the most important explanatory factor and was significantly associated with parental acceptance of varicella vaccination in 2009 to 2011 (adjusted OR 11.5; 95%CI 3.6-36.3 (2009), 26.7; 95%CI 5.4-132.2 (2010) and 12.7; 95%CI 3.9-41.4 (2011)). Conclusions: From 2009 to 2011, first dose VV coverage further increased by approximately 15% up to 68%, corresponding with the increased use of MMRV. Although parental acceptance had increased, first dose coverage for varicella was still considerably lower than coverage for measles in 2011. Physician's recommendation of VV was the only independent factor significantly associated with parental acceptance in all study years. A further increase in varicella vaccination coverage is necessary in order to avoid potential negative effects such as an increase in the mean age of children getting infected with varicella. Therefore, information campaigns for both parents and physicians are urgently needed.

Reduction of residual amplitude modulation to 1 × 10⁻6 for frequency modulation and laser stabilization.

Active control and cancellation of residual amplitude modulation (RAM) in phase modulation of an optical carrier is one of the key technologies for achieving the ultimate stability of a laser locked to an ultrastable optical cavity. Furthermore, such techniques are versatile tools in various frequency modulation-based spectroscopy applications. In this Letter we report a simple and robust approach to actively stabilize RAM in an optical phase modulation process. We employ a waveguide-based electro-optic modulator (EOM) to provide phase modulation and implement an active servo with both DC electric field and temperature feedback onto the EOM to cancel both the in-phase and quadrature components of the RAM. This technique allows RAM control on the parts-per-million level where RAM-induced frequency instability is comparable to or lower than the fundamental thermal noise limit of the best available optical cavities.

Administration of lopinavir/ritonavir association during rat pregnancy: maternal and fetal effects.

PURPOSE: To evaluate the effects of the association of lopinavir and ritonavir administered during the whole period of rat pregnancy. METHODS: 62 Wistar rats of the EPM-1 variant weighing about 200 g were randomly divided into five groups: two controls (Ctrl = stress control, n = 10; and Ctr2 = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of lopinavir/ritonavir (Exp1 = 12.8/3.2 mg/kg b.w., n = 14; Exp2 = 38.4/9.6 mg/kg b.w., n = 14; Exp3 = 115.2/28.8 mg/kg b.w., n = 14) from 'day 0' up to the 20th day of pregnancy. Maternal body weight was recorded at the start of the experiment and on the 7th, 14th and 20th day thereafter. At term (20th day), upon laparotomy and hysterotomy, the rats were anesthetized and the amount of implantations, reabsorptions, living fetuses, placentae and intrauterine deaths were recorded. The collected fetuses and placentae were weighed and the concepts were examined under a stereoscope microscope for external malformations. RESULTS: An apparent dose-unrelated lethal effect of the antiviral association on the pregnant rats was observed; notwithstanding, the body weight gain of the surviving rats had no changes, independent of the considered group. It was noted that the quantitative and qualitative intrauterine content of living term rats was indistinguishable from that of the controls. CONCLUSION: There was some degree of deleterious effects of the administration of the lopinavir/ritonavir association on pregnant rats; such effects eventually led to maternal death. However, neither the surviving rats showed toxicity nor did their concepts present any detectable change which could be related to the drug association.

Observation of two-neutrino double-beta decay in 136Xe with the EXO-200 detector.

We report the observation of two-neutrino double-beta decay in (136)Xe with T(1/2) = 2.11 ± 0.04(stat) ± 0.21(syst) × 10(21) yr. This second-order process, predicted by the standard model, has been observed for several nuclei but not for (136)Xe. The observed decay rate provides new input to matrix element calculations and to the search for the more interesting neutrinoless double-beta decay, the most sensitive probe for the existence of Majorana particles and the measurement of the neutrino mass scale.

A magnetically driven piston pump for ultra-clean applications.

A magnetically driven piston pump for xenon gas recirculation is presented. The pump is designed to satisfy extreme purity and containment requirements, as is appropriate for the recirculation of isotopically enriched xenon through the purification system and large liquid xenon time projection chamber of EXO-200. The pump, using sprung polymer gaskets, is capable of pumping more than 16 standard liters per minute of xenon gas with 750 Torr differential pressure.

A simple radionuclide-driven single-ion source.

We describe a source capable of producing single barium ions through nuclear recoils in radioactive decay. The source is fabricated by electroplating (148)Gd onto a silicon α-particle detector and vapor depositing a layer of BaF(2) over it. (144)Sm recoils from the alpha decay of (148)Gd are used to dislodge Ba(+) ions from the BaF(2) layer and emit them in the surrounding environment. The simultaneous detection of an α particle in the substrate detector allows for tagging of the nuclear decay and of the Ba(+) emission. The source is simple, durable, and can be manipulated and used in different environments. We discuss the fabrication process, which can be easily adapted to emit most other chemical species, and the performance of the source.

Effects of lopinavir-ritonavir combined therapy during the rat pregnancy. Morphological and biochemical aspects.

OBJECTIVE: To evaluate the biochemical and morphological effects in rats subjected to three different dose associations of the protease inhibitors lopinavir and ritonavir administered throughout the entire period of pregnancy. STUDY DESIGN: The animals were treated throughout pregnancy with daily oral doses of lopinavir+ritonavir starting at the day one of pregnancy, and were divided into four groups: E1, 13.3+3.3 mg/kg; E2, 39.9+9.9 mg/kg; E3, 119.7+29.9 mg/kg and C, control (drug vehicle, propyleneglycol). The animals were then sacrificed and maternal blood and fetal and maternal organ samples were taken for morphological and biochemical analysis. RESULTS: No major changes were identified in the group treated with the lowest dose as compared with the control. In the group E2, we found hepatocytes with signs of atrophy, eosinophilic cytoplasm, picnotic nuclei and vasodilatation. The proximal convoluted tubules of maternal kidneys showed eosinophilic areas and hyperchromatic nuclei, as well as signs of vasodilation. In the group treated with the highest dose (group E3), in the maternal kidneys and livers, the morphological changes were similar to those found in E2, although more prominent. Regarding the fetal organs, the single abnormality observed was some liver vasodilation in the group E3 (highest dose). The treatment with lopinavir+ritonavir caused discrete, yet significant, alterations of aspartate aminotransferase activity, blood urea nitrogen and creatinine plasma levels. CONCLUSIONS: Our results showed that the administration of a combination of lopinavir plus ritonavir to pregnant rats can cause morphological as well as functional changes in maternal and fetal liver and kidneys and, in higher than therapeutic doses, might be toxic to those animals.

Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood.

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

The ups and downs of MEK kinase interactions.

MEK kinases (MEKKs) comprise a family of related serine-threonine protein kinases that regulate mitogen-activated protein kinase (MAPK) signalling pathways leading to c-Jun NH2-terminal kinase (JNK) and p38 activation, induced by cellular stress (e.g., UV and gamma irradiation, osmotic stress, heat shock, protein synthesis inhibitors), inflammatory cytokines (e.g., tumour necrosis factor alpha, TNFalpha, and interleukin-1, IL1) and G protein-coupled receptor agonists (e.g., thrombin). These stress-activated kinases have been implicated in apoptosis, oncogenic transformation, and inflammatory responses in various cell types. At present, the signalling events involving MEKKs are not well understood. This review summarises our current knowledge concerning the regulation and function of MEKK family members, with particular emphasis on those factors capable of directly interacting with distinct MEKK isoforms.

Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes.

Variation in the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene may play a role in the development of type 2 diabetes mellitus. Therefore we investigated the association between the P12A and c1431t polymorphisms in the PPAR gamma gene and type 2 diabetes. The incidence of the P12A polymorphism was determined by PCR-RFLP and the c1431t by single-strand conformation polymorphism analysis in 219 patients with, and 429 without type 2 diabetes. The frequency of the A allele of P12A polymorphism was 0.16 and the t allele of c1431t polymorphism, 0.13 in patients with type 2 diabetes, and 0.13 and 0.12 respectively in subjects without diabetes 3.2% of patients with and 1.4% without type 2 diabetes were A12A. Since the polymorphisms are not linked the association of the 9 possible genotypes with type 2 diabetes was determined. All patients with genotype A12A/c1431c had type 2 diabetes (n = 3, p = 0.038). There was no association between A12A/t1431t and diabetes. DNA sequencing revealed no additional mutations in the coding region of the PPAR gamma gene in genotypes A12A/c1431c or A12A/t1431t. The associations found between polymorphisms in the PPAR gamma gene and type 2 diabetes suggest that either the A12 isofrom is functional leading to a predisposition to type 2 diabetes in homozygotes or that there is a third, unknown mutation linked to the A12/c1431 haplotype which is responsible.

Isotype-specific functions of Raf kinases.

The family of Raf-protein kinases consisting of A-Raf, B-Raf, and c-Raf-1 is involved in cellular processes which regulate proliferation, differentiation, and apoptosis. Cell-culture experiments and the knockout of individual Raf genes suggested that the three Raf isoforms have overlapping and unique regulatory functions. However, it is not known how these isotype-specific functions of Raf kinases occur in the cell. Published data suggest that Raf proteins might differ in the regulation of their activation as well as in their ability to connect to downstream signaling pathways. Since Raf is part of a multiprotein complex and protein-protein interactions are important for Raf signaling, we propose that isotype-specific functions can be achieved by isotype-restricted protein binding. Recently we were able to identify candidates for such Raf-isoform-specific interaction partners.

Interaction between the protein kinase B-Raf and the alpha-subunit of the 11S proteasome regulator.

Protein kinases of the Raf family act as signal-transducing elements downstream of activated cell surface receptors and are involved in the regulation of proliferation, differentiation, and cell survival. Whereas the role of c-Raf-1 as a mitogen-activated protein/extracellular signal-regulated kinase activator within the mitogenic cascade is well established, less is known about the mammalian Raf isoforms A-Raf and B-Raf. Here we report that B-Raf binds to PA28alpha, one of two subunits of the 11S regulator of proteasomes. PA28alpha was isolated as a B-Raf-binding protein in a yeast two-hybrid screen of a PC12 cDNA library. Both proteins can be coimmunoprecipitated after transient expression in 293 cells. No association could be found between PA28alpha and A-Raf or c-Raf-1. B-Raf binds to a region in PA28alpha that is important for its proteasome-activating function.

The regulatory subunit of protein kinase CK2 is a specific A-Raf activator.

Two protein kinases that are involved in proliferation and oncogenesis but so far were thought to be functionally independent are Raf and CK2. The Raf signaling pathway is known to play a critical role in such fundamental biological processes as cellular proliferation and differentiation. Abnormal activation of this pathway is potentially oncogenic. Protein kinase CK2 exhibits enhanced levels in solid human tumors and proliferating tissue. In a two-hybrid screen of a mouse-embryo cDNA library we detected an interaction between A-Raf and CK2beta subunit. This binding was specific, as no interaction between CK2beta and B-Raf or c-Raf-1 was observed. Regions critical for this interaction were localized between residues 550 and 569 in the A-Raf kinase domain. A-Raf kinase activity was enhanced 10-fold upon coexpression with CK2beta in Sf9 cells. The alpha subunit of CK2 abolishes this effect. This is the first demonstration of both a direct Raf-isoform-specific activation and a regulatory role for CK2beta independent of the CK2alpha subunit. The present data thus link two different protein kinases that were thought to work separately in the cell.

Interlaboratory assessment of the bovine corneal opacity and permeability (BCOP) assay.

A multinational interlaboratory study to investigate the bovine corneal opacity and permeability (BCOP) assay is presented. The aim of this work was to determine the capability and possible limitations of this method to predict ocular irritancy of a large set of chemicals. The assays were carried out in 12 European laboratories with different types of activity. In each of these laboratories 52 substances, with a wide range of structure, physical form and irritant properties, were tested and in vitro scores were compared with those obtained from concurrent rabbit eye (Draize) tests. The technique was easily learned by workers in the participating laboratories, as shown by the fact that there were consistent responses between treated corneas within an individual laboratory. Interlaboratory variability was also very good. It was found that a given laboratory had a 96% chance of classifying irritants or non-irritants similarly to the other laboratories. In addition, it was observed that corneas preserved overnight responded similarly to freshly prepared tissues, thus allowing flexibility for those laboratories where the availability of corneas is limited. Comparisons between in vivo and in vitro data showed that the BCOP data correctly predicted whether a compound would be irritating or non-irritating for 44 of the 52 compounds (84.6%). Specificity and sensitivity were also greater than 84%, and the same number of substances were overestimated as were underestimated (four out of 52). All of the false negatives were solids whereas most of false positives were liquids, indicating that some adjustment in the protocol may be required depending on the physical state of the substance to be tested. All of the substances selected could be evaluated, with no limitation such as colour, insolubility, low or high pH. Given the number of products evaluated and the reproducibility within and among the laboratories involved, the overall results are quite satisfactory and therefore confirm the usefulness of the assay for screening chemicals for ocular irritation.

Characterization of the transport of tri- and dicarboxylates by pig intestinal brush-border membrane vesicles.

1. Transport of citrate and fumarate across the pig intestinal brush-border membrane (BBM) was investigated using isolated BBM vesicles. 2. Citrate and fumarate uptake was stimulated by an inwardly directed Na+ gradient consistent with Na+/citrate (fumarate) co-transport. Cis-inhibition and trans-stimulation experiments strongly suggest the existence of a common transport site for tri- and dicarboxylates. 3. The protonated forms of citrate (citrate-1, citrate-2) seem to be much better transported than citrate-3, indicated by the strong stimulation of citrate uptake at an extravesicular pH of 5.6 compared to pH 7.8. 4. Uptake of tri- and dicarboxylates seems to be potential-sensitive since citrate and in particular fumarate transport was enhanced by an inside negative potential difference. 5. Kinetics of succinate transport revealed a single carrier-mediated component with apparent kinetic constants of 0.43 nmol/mg protein-3 s (Vmax) and 0.14 mmol/l (Km).

Regression of high-affinity carrier-mediated intestinal transport of taurine in adult cats.

The sulfur-containing beta-amino acid taurine is an essential nutrient for cats. Owing to some metabolic peculiarities, cats are more dependent on dietary sources of taurine than other mammals. We therefore studied taurine uptake by intestinal brush-border membrane vesicles (BBMV) isolated from cat small intestine. Taurine uptake by feline BBMV was not influenced by a transmembrane Na+ gradient compared with Na(+)-free conditions. Kinetic analysis of initial taurine uptake yielded no evidence for a carrier-mediated transport process. These findings cannot be attributed to an overall inability of cumulative substrate uptake in our vesicle preparations because D-glucose uptake was strongly Na+ dependent, showing the overshoot phenomenon typically associated with active transport in vesicle experiments. Furthermore, L-leucine transport was mediated by a single Na(+)-dependent carrier mechanism (maximal transport velocity 1.2 nmol.mg protein-1.s-1, Km = 2.1 mM). In contrast to taurine uptake by feline BBMV, transport of taurine by pig intestinal BBMV was markedly enhanced by an inwardly directed Na+ gradient. Thus, differing from other mammalian species, taurine uptake across the intestinal brush-border membrane of the adult cat seems not to be mediated by a specific transport mechanism. Therefore taurine absorption from the gastrointestinal tract will possibly become a limiting factor for maintenance of taurine homeostasis in the cat under conditions of decreased dietary taurine intake.