TB among refugees from Ukraine in European countries.

BACKGROUND: Since the Russian Federation's invasion of Ukraine, millions of refugees have moved to neighbouring European countries. We assessed the burden of TB in these refugees and surveyed screening approaches. METHODS: We conducted a survey among 30 European Union/European Economic Area and 13 other European countries, requesting population data on migrant residents and refugees with country of birth (COB) Ukraine, the number of TB notifications among people with COB Ukraine and countries' screening policies for refugees from Ukraine. RESULTS: In 2021, the number of migrants born in Ukraine was 1.7 million in the 34 responding countries, and increased with 5.2 million refugees from Ukraine to 6.9 million in 2022. These countries notified 207 TB cases in people with COB Ukraine in 2021 (TB notification rate 12.0/100,000) and 887 in 2022 (TB notification rate 12.8/100,000), of which 228 (26%) had multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). TB notification rates were higher in countries advising screening for all (16.9/100,000) or specific groups of refugees from Ukraine (14.7/100,000) compared to those without screening (7.2/100,000). CONCLUSION: TB rates found in people from Ukraine were lower than the expected rate of 44 per 100,000, but higher in host countries recommending screening. Our study underscores the need for adequate TB health services for refugees from Ukraine to ensure tailored diagnosis and treatment, especially for MDR/RR-TB.

CONTEXTE: Suite à l'invasion de l'Ukraine par la Fédération de Russie, des millions de réfugiés se sont installés dans les pays européens voisins. Notre étude a porté sur la prévalence de la TB parmi ces réfugiés et a examiné les différentes méthodes de dépistage. MÉTHODES: Nous avons réalisé une enquête auprès de 30 pays de l'Union européenne/de l'Espace économique européen et de 13 autres pays européens, en demandant des données démographiques sur les résidents migrants et les réfugiés dont le pays de naissance (COB, pour l'anglais « country of birth ¼) est l'Ukraine, le nombre de notifications de TB chez les personnes dont le COB est l'Ukraine et les politiques de dépistage des pays pour les réfugiés d'Ukraine. RÉSULTATS: En 2021, le nombre de migrants nés en Ukraine était de 1,7 million dans les 34 (79%) pays ayant répondu à l'enquête, et a augmenté à 5,2 millions en 2022. Ces pays ont notifié 207 cas de TB chez des personnes ayant le COB Ukraine en 2021 (taux de notification de la TB 12,0/100 000) et 887 en 2022 (taux de notification de la TB 12,8/100 000), dont 228 (26%) avaient une TB multirésistante/résistante à la rifampicine (MDR/RR-TB). Les pays qui recommandent le dépistage pour tous ont enregistré des taux de notification de la TB plus élevés (16,9/100 000) tandis que ceux qui ciblent des groupes spécifiques de réfugiés ukrainiens ont signalé (14,7/100 000). En revanche, les pays ne proposant pas de dépistage ont affiché un taux de notification de seulement (7,2/100 000). CONCLUSION: Les personnes originaires d'Ukraine présentaient des taux de TB inférieurs à ceux attendus, soit 44 pour 100 000, tandis que les pays d'accueil recommandant le dépistage affichaient des taux plus élevés. Notre étude met en évidence l'importance de fournir des services de santé appropriés pour la TB aux réfugiés ukrainiens, afin d'assurer un diagnostic et un traitement adaptés, en particulier pour la MDR/RR-TB.

Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals.

BACKGROUND: While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS: We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS: 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS: The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.

[The New WHO Guidelines for Rapid Diagnostics and Treatment of Drug-Resistant Tuberculosis Commented for Germany, Austria and Switzerland]. / Die neuen WHO-Empfehlungen für schnelle Diagnostik und Therapie resistenter Tuberkulose in Deutschland, Österreich und der Schweiz.

The increasing evidence has made it necessary to change international recommendations for the diagnosis and treatment of resistant tuberculosis repeatedly in the recent years. This year, the WHO has published comprehensive recommendations that take into account these developments. The current German tuberculosis guideline was published in 2017 with differing recommendations in some areas. Here the new WHO recommendations of 2020 for rapid diagnosis and therapy of resistant tuberculosis are summarized and the relevant differences are commented for Germany, Austria and Switzerland. A complete re-evaluation of the literature is currently taking place by updating the German-language AWMF 2k guidelines.

[Migration and Tuberculosis]. / Migration und Tuberkulose.

The majority of the people suffering from tuberculosis in Germany are migrants. The treatment of this demographic still presents certain challenges. Only up to a quarter to a fifth of tuberculosis cases in migrants is being diagnosed by the screening methods that were implemented by The German Protection against Infection Act (Infektionsschutzgesetz, IfSG). Reactivation of latent tuberculosis is the most common cause for tuberculosis in migrants. Easy access to health care is vital for the testing and treatment of latent tuberculosis in people with a high risk of reactivation. The level of infection risk, comorbidities and presentation of disease vary depending on the country of origin. Especially during migration people are more susceptible to somatic and mental maladies. Extrapulmonary tuberculosis is frequent in migrants and requires specific diagnostic approaches. Where risk factors for a multi-drug-resistant tuberculosis are present, this condition has to be actively excluded. To facilitate diagnosis and therapy of tuberculosis in migrants a high level of trust has to be established in the doctor-patient relationship. Therefore and despite of cultural and linguistic differences empathy and time are key. Patients need to be encouraged to complete their treatment rather than terminate it prematurely. To that end comorbidities have also to be diagnosed and treated, social and legal aspects have to be considered.

Normal faulting in central Tibet since at least 13.5 Myr ago.

Tectonic models for the evolution of the Tibetan plateau interpret observed east-west thinning of the upper crust to be the result of either increased potential energy of elevated crust or geodynamic processes that may be unrelated to plateau formation. A key piece of information needed to evaluate these models is the timing of deformation within the plateau. The onset of normal faulting has been estimated to have commenced in southern Tibet between about 14 Myr ago and about 8 Myr ago and, in central Tibet, about 4 Myr ago. Here, however, we report a minimum age of approximately 13.5 Myr for the onset of graben formation in central Tibet, based on mineralization ages determined with Rb-Sr and 40Ar-39Ar data that post-date a major graben-bounding normal fault. These data, along with evidence for prolonged activity of normal faulting in this and other Tibetan grabens, support models that relate normal faulting to processes occurring beneath the plateau. Thinning of the upper crust is most plausibly the result of potential-energy increases resulting from spatially and temporally heterogeneous changes in thermal structure and density distribution within the crust and upper mantle beneath Tibet. This is supported by recent geophysical and geological data, which indicate that spatial heterogeneity exists in both the Tibetan crust and lithospheric mantle.

Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice.

Cyclic nucleotide-gated ion channels in olfactory sensory neurons (OSNs) are hypothesized to play a critical role in olfaction. However, it has not been demonstrated that the cAMP signaling is required for olfactory-based behavioral responses, and the contributions of specific adenylyl cyclases to olfaction have not been defined. Here, we report the presence of adenylyl cyclases 2, 3, and 4 in olfactory cilia. To evaluate the role of AC3 in olfactory responses, we disrupted the gene for AC3 in mice. Interestingly, electroolfactogram (EOG) responses stimulated by either cAMP- or inositol 1,4,5-triphosphate- (IP3-) inducing odorants were completely ablated in AC3 mutants, despite the presence of AC2 and AC4 in olfactory cilia. Furthermore, AC3 mutants failed several olfaction-based behavioral tests, indicating that AC3 and cAMP signaling are critical for olfactory-dependent behavior.

Xylose utilisation: cloning and characterisation of the Xylose reductase from Candida tenuis.

Xylose reductases catalyse the initial reaction in the xylose utilisation pathway, the NAD(P)H+H+ dependent reduction of xylose to xylitol. In this work, the xylose reductase gene from Candida tenuis CBS 4435 was cloned and successfully expressed in E. coli. From the purified and partially sequenced protein primers were deduced for PCR. The fragment obtained was used for Southern blot analysis and screening of a subgenomic library. The clone containing the open reading frame was sequenced; the gene consisted of 969 nucleotides coding for a 322 amino acids protein with a molecular mass of 36 kDa. Putative regulatory signals were identified with the help of a Saccharomyces cerevisiae regulatory sequence database. In order to express the xylose reductase in E. coli, the gene was placed under positive and negative control. At low temperatures, the xylose reductase was expressed in soluble and active form up to about 10% of the soluble protein; with rising temperatures formation of visible inclusion bodies occurred. In refolding experiments we were able to recover the major portion of xylose reductase activity from the pellet fraction.

Regulation and immunohistochemical localization of betagamma-stimulated adenylyl cyclases in mouse hippocampus.

Specific forms of synaptic plasticity such as long-term potentiation (LTP) are modulated by or require increases in cAMP. The various adenylyl cyclase isoforms possess unique regulatory properties, and thus cAMP increases in a given cell type or tissue in response to converging signals are subject to the properties of the adenylyl cyclase isoforms expressed. In most tissues, adenylyl cyclase activity is stimulated by neurotransmitters or hormones via stimulatory G-protein (Gs)-coupled receptors and is inhibited via inhibitory G-protein (Gi)-linked receptors. However, in the hippocampus, stimulation of Gi-coupled receptors potentiates Gs-stimulated cAMP levels. This effect may be associated with the regulatory properties of adenylyl cyclase types 2 and 4 (AC2 and AC4), isoforms that are potentiated by the betagamma subunit of Gi in vitro. Although AC2 has been shown to be stimulated by betagamma in whole cells, reports describing the sensitivity of AC4 to betagamma in vivo have yet to emerge. Our results demonstrate that Gs-mediated stimulation of AC4 is potentiated by betagamma released from activated Gi-coupled receptors in intact human embryonic kidney (HEK) 293 cells. Furthermore, we show that the AC2 and AC4 proteins are expressed in the mouse hippocampal formation and that they colocalize with MAP2, a dendritic and/or postsynaptic marker. The presence of AC2 and AC4 in the hippocampus and the ability of each of these enzymes to detect coincident activation of Gs- and Gi-coupled receptors suggest that they may play a crucial role in certain forms of synaptic plasticity by coordinating such overlapping synaptic inputs.

Impaired cerebellar long-term potentiation in type I adenylyl cyclase mutant mice.

Activation of adenylyl cyclase and the consequent production of cAMP is a process that has been shown to be central to invertebrate model systems of information storage. In the vertebrate brain, it has been suggested that a presynaptic cascade involving Ca influx, cAMP production, and subsequent activation of cAMP-dependent protein kinase is necessary for induction of long-term potentiation (LTP) at the cerebellar parallel fiber-Purkinje cell synapse. We have used mutant mice in which the major Ca-sensitive adenylyl cyclase isoform of cerebellar cortex (type I) is deleted to show that this results in an approximately 65% reduction in cerebellar Ca-sensitive cyclase activity and a nearly complete blockade of cerebellar LTP assessed using granule cell-Purkinje cell pairs in culture. This blockade is not accompanied by alterations in a number of basal electrophysiological parameters and may be bypassed by application of an exogenous cAMP analog, suggesting that it results specifically from deletion of the type I adenylyl cyclase.

Cloning, chromosomal mapping, and regulatory properties of the human type 9 adenylyl cyclase (ADCY9).

The type 9 adenylyl cyclase (AC9) is a widely distributed adenylyl cyclase that was originally cloned from a mouse cDNA library. Here we report the cloning, chromosomal mapping, and regulatory properties of human AC9 (HGMW-approved symbol ADCY9). Although the human AC9 sequence shows 86% homology with mouse AC9, divergence at the C2a/C2b junction results in an alternative C2b amino acid sequence. In situ hybridization localized the human AC9 gene to both human and mouse chromosomes 16. AC9 mRNA is present in all tissues examined, with the highest levels found in skeletal muscle, heart, and brain. To characterize the regulatory properties of human AC9 in vivo, the enzyme was expressed in HEK-293 cells. Human AC9 is stimulated by beta-adrenergic receptor activation but is insensitive to forskolin, Ca2+ and somatostatin. In contrast to mouse AC9, the activity of human AC9 is unaffected by inhibitors of calcineurin. These data emphasize the importance of determining the regulatory properties of human adenylyl cyclases.

Sensitization of olfactory guanylyl cyclase to a specific imprinted odorant in coho salmon.

The role of cGMP in olfactory signaling is not fully understood, but it is believed to play a modulatory role in intracellular signaling in vertebrate olfactory receptor neurons (ORNs). Here, we present evidence that cGMP in ORNs may play an important role in recognition of biologically relevant odors and olfactory learning. Specifically, we investigated the cellular mechanisms underlying olfactory imprinting in salmon. Salmon learn odors associated with their natal site as juveniles and later use these odors to guide their homing migration. This imprinting is believed to involve sensitization of the peripheral olfactory system to specific homestream odorants. We imprinted juvenile salmon to the odorant beta-phenylethyl alcohol (PEA) and examined the sensitivity of olfactory adenylyl and guanylyl cyclases to PEA during development. Stimulation of guanylyl cyclase activity by PEA was significantly greater in olfactory cilia isolated from PEA-imprinted salmon compared with PEA-naive fish only at the time of the homing migration, 2 years after PEA exposure. These results suggest that sensitization of olfactory guanylyl cyclase may play an important role in olfactory imprinting by salmon.

Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer.

PURPOSE: We investigated quality and efficacy criteria of an autologous, physically and immunologically purified, Newcastle disease virus (NDV)-modified, irradiated tumor-cell vaccine (ATV-NDV) by analyzing three independent cohorts (a through c) of patients vaccinated between 1991 and 1995. MATERIALS AND METHODS: Included were 63 patients with primary breast cancer (a), 27 with metastatic pretreated breast cancer (b), and 31 with metastatic pretreated ovarian cancer (c). In addition to vaccine, cohorts b and c received nonspecific immunotherapy as supportive treatment. After cryoconservation and purification, the vaccines varied in applied numbers of viable cells and dead cell contaminations. We retrospectively hypothesized that an immunogenic vaccine should contain at least 1.5 x 10(6) viable tumor cells and viability should be at least 33%. Each cohort was thus divided into two groups; one that received vaccine type A (A), fulfilling both criteria; and the other type B (B), missing one or both criteria. RESULTS: Conventional prognostic factors were wall balanced between A and B in cohorts a and c. In cohort a, there was a benefit in survival (P = .026) and disease-free survival (P = .089) for A. In addition, in cohort a, the relative risk of dying in the group that received A as compared with B was 0.2 (univariate Cox model). There were also survival trends in favor of A versus B (P = .18 and P = .09, respectively) in cohorts b and c, with relative risks of 0.5 and 0.42, respectively. In cohort b, the survival benefit could not be ascribed to vaccine quality alone, because of prognostic imbalance in favor of A. CONCLUSION: In cohort c, like in cohort a, the survival benefit for A may be ascribed to the ATV-NDV vaccine quality, since prognostic factors were not biased. This could imply clinical effectivity in breast and ovarian cancer with ATV-NDV high-quality vaccine. Furthermore, the data provide clinically relevant information for standardization and quality control of autologous tumor-cell vaccines. A randomized study is urgently needed.