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.

Key drivers of the TB epidemic in Suriname and priority actions to reduce incidence and mortality.

BACKGROUND: The WHO has recently published updated guidance for national strategic planning for TB. To address the TB epidemic comprehensively, it is necessary to conduct an epidemiological review as part of the situation analysis in the national strategic plan. METHODS: A descriptive epidemiological study was conducted using data from the national TB register for the period of 2010-2020. Simple frequencies were calculated for demographic and clinical variables. Trends in TB notification rates for the period 2010-2020 were also calculated. RESULTS: TB notification rates between 2011 (24.3/100,000) and 2019 (23.9/100,000) remained almost the same. The HIV status was known for 97.1% of TB cases, 22.7% of whom had HIV co-infection; 10.9% of patients with detected Mycobacterium tuberculosis were also resistant to rifampicin. Case fatality rate for all cases was 13.0%. Of the identified contacts, 66% were screened; 28.3-47.5% of those with TB infection started treatment, 63.3-75.9% of whom completed treatment. CONCLUSION: The review identified the following areas of concern: no decline in TB rates, high proportion of TB-HIV co-infection, high rate of resistance to rifampicin, high case-fatality rates and suboptimal contact investigation care cascade . The review was used to inform interventions and key actions to reduce TB morbidity and mortality in Suriname.

CONTEXTE: L'OMS a récemment publié des orientations actualisées pour la planification stratégique nationale de la TB. Pour faire face à l'épidémie de TB de manière globale, il est nécessaire de procéder à un examen épidémiologique dans le cadre de l'analyse de la situation du plan stratégique national. MÉTHODES: Une étude épidémiologique descriptive a été réalisée à partir des données du registre national de la TB pour la période 2010­2020. Des fréquences simples ont été calculées pour les variables démographiques et cliniques. Les tendances des taux de notification de la TB pour la période 2010­2020 ont également été calculées. RÉSULTATS: Les taux de notification de la TB entre 2011 (24,3/100 000) et 2019 (23,9/100 000) sont restés pratiquement les mêmes. Le statut VIH était connu pour 97,1% des cas de TB, dont 22,7% présentaient une co-infection par le VIH ; 10,9% des patients chez qui Mycobacterium tuberculosis avait été détecté étaient également résistants à la rifampicine. Le taux de létalité pour l'ensemble des cas était de 13,0%. Parmi les contacts identifiés, 66% ont fait l'objet d'un dépistage ; 28,3­47,5% des personnes infectées par la TB ont entamé un traitement, et 63,3­75,9% d'entre elles l'ont achevé. CONCLUSION: L'étude a permis d'identifier les domaines de préoccupation suivants : absence de baisse des taux de TB, proportion élevée de co-infection TB-VIH, taux élevé de résistance à la rifampicine, taux élevé de létalité et cascade de soins sous-optimale en matière d'investigation des contacts. L'étude a été utilisée pour informer les interventions et les actions clés visant à réduire la morbidité et la mortalité dues à la TB au Suriname.

Diagnosis, treatment and transmission of rifampicin-resistant TB in the Netherlands, 2010-2019.

BACKGROUND: New tools for diagnosis and treatment of rifampicin-resistant (RR-) and multidrug-resistant (MDR-) TB have become available in the last decade, including better tests confirming transmission.OBJECTIVE: To analyse transmission risks of MDR/RR-TB in the Netherlands.METHODS: Analysis of national data of patients with MDR/RR-TB notified in 2010-2019, including contact investigation and genotyping data.RESULTS: Patients with MDR/RR-TB (n = 121) were more often female (adjusted odds ratio [aOR] 1.5), foreign-born, previously treated for TB (aOR 5.2) and co-infected with HIV (aOR 2.3) than patients with no MDR/RR-TB. Treatment outcomes were satisfactory, with at least 79% completing treatment. After additional whole-genome sequencing (WGS), five molecular clusters of 16 patients remained. Patients in three clusters could not be epidemiologically linked and were unlikely to have been infected in the Netherlands. The remaining eight (6.6%) patients with MDR/RR-TB belonged to two clusters, and were likely the result of transmission in the Netherlands. Among close contacts of patients with smear-positive pulmonary MDR/RR-TB, 13.4% (n = 38) had TB infection and 1.1% (n = 3) had TB disease. Only six contacts with TB infection were treated with a quinolone-based preventive treatment regimen.CONCLUSION: MDR/RR-TB is effectively controlled in the Netherlands. Preventive treatment options could be considered more frequently in contacts clearly infected by an index patient with MDR-TB.

Large B-cell Lymphomas of Immune-Privileged Sites Relapse via Parallel Clonal Evolution from a Common Progenitor B Cell.

Large B-cell lymphoma of immune-privileged sites (LBCL-IP) arise in immune sanctuaries including the testis and central nervous system (CNS). After initially reaching complete response, relapses occur in almost 50% of patients, typically at other immune-privileged sites. Resolution of the clonal relationships and evolutionary patterns of LBCL-IP is required to understand the unique clinical behavior. We collected a unique set of 33 primary-relapse LBCL-IP sample pairs and performed next-generation sequencing for copy number, mutation, translocation, and immunoglobulin clonality analysis. All LBCL-IP sample pairs were clonally related, and both tumors developed from a common progenitor cell (CPC) with MYD88 and TBL1XR1 mutations and/or BCL6 translocations in 30/33 cases, indicating that these are early genetic events. This was succeeded by intermediate genetic events including shared, as well as unique alterations in targets of aberrant somatic hypermutation (aSHM), CD79B mutations, and 9p21.3/CDKN2A loss. Genetic alterations in genes involved in immune escape (HLA, CD274/PDCD1LG2) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center reentry, aSHM and immune escape. SIGNIFICANCE: Genomic analyses reveal that primary and relapse LBCL-IP originate from a common progenitor cell with a small set of genetic alterations, followed by extensive parallel diversification, elucidating the clonal evolution of LBCL-IP.

The path towards consensus genome classification of diffuse large B-cell lymphoma for use in clinical practice.

Diffuse large B-cell lymphoma (DLBCL) is a widely heterogeneous disease in presentation, treatment response and outcome that results from a broad biological heterogeneity. Various stratification approaches have been proposed over time but failed to sufficiently capture the heterogeneous biology and behavior of the disease in a clinically relevant manner. The most recent DNA-based genomic subtyping studies are a major step forward by offering a level of refinement that could serve as a basis for exploration of personalized and targeted treatment for the years to come. To enable consistent trial designs and allow meaningful comparisons between studies, harmonization of the currently available knowledge into a single genomic classification widely applicable in daily practice is pivotal. In this review, we investigate potential avenues for harmonization of the presently available genomic subtypes of DLBCL inspired by consensus molecular classifications achieved for other malignancies. Finally, suggestions for laboratory techniques and infrastructure required for successful clinical implementation are described.

TB in migrants residing in the Netherlands for at least 5 years at diagnosis, 2003-2018.

BACKGROUND: One of the challenges of TB elimination in low-incidence countries is the relatively high incidence of TB in migrants in these countries, even after multiple years of residence.OBJECTIVE: To describe and compare TB incidence and characteristics of migrant TB patients residing in the Netherlands for at least (≥)5 years at diagnosis with non-foreign-born TB patients in order to identify additional strategies that could reduce TB incidence in the former group.METHODS: A retrospective cohort study was conducted in migrants from Somalia, Morocco, Suriname, Turkey and Indonesia who were diagnosed with TB in the Netherlands in 2003-2018. TB incidences were calculated and multivariate logistic regression was used to identify differences in characteristics of TB patients per country of birth compared to non-foreign-born patients.RESULTS: TB incidence was highest in individuals from Somalia (162.5/100,000 population in 2018), followed by individuals from Morocco (37.1/100,000). In the non-foreign-born population, TB incidence was 1.2/100,000. Differences in characteristics of TB patients compared to non-foreign-born patients varied by country of birth.CONCLUSION: Our findings underline the importance of being aware of the heterogeneity of TB incidence and characteristics of patients in the migrant population residing ≥5 years in the Netherlands.

Country differences and determinants of yield in programmatic migrant TB screening in four European countries.

INTRODUCTION The WHO End TB Strategy emphasises early diagnosis and screening of TB in high-risk groups, including migrants. We analysed TB yield data from four large migrant TB screening programmes to inform TB policy.METHODS We pooled routinely collected individual TB screening episode data from Italy, the Netherlands, Sweden and the United Kingdom under the European Union Commission E-DETECT.TB grant, described characteristics of the screened population, and analysed TB case yield.RESULTS We collected data on 2,302,260 screening episodes among 2,107,016 migrants, mostly young adults aged 18-44 years (77.8%) from Asia (78%) and Africa (18%). There were 1,658 TB cases detected through screening, with substantial yield variation (per 100,000): 201.1 for Sweden (95% confidence intervals CI 111.4-362.7), 68.9 (95% CI 65.4-72.7) for the United Kingdom, 83.2 (95% CI 73.3-94.4) for the Netherlands and 653.6 (95% CI 445.4-958.2) in Italy. Most TB cases were notified among migrants from Asia (n = 1,206, 75/100,000) or Africa (n = 370, 76.4/100,000), and among asylum seekers (n = 174, 131.5/100,000), migrants to the Netherlands (n = 101, 61.9/100,000) and settlement visa migrants to the United Kingdom (n = 590, 120.3/100,000).CONCLUSIONS We found considerable variations in yield across programmes, types of migrants and country of origin. These variations may be partly explained by differences in migration patterns and programmatic characteristics.

Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV.

Although the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR] <0.001) were more frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68+/CD163+ macrophages (P < .001), BCL2 translocation (BCL2trl+) (P < .0001), and KMT2D (FDR = 0.003) and CREBBP (FDR = 0.04) mutations were found more frequently in stage III/IV FL. Using clustering, we identified 3 clusters within stage I, and 2 clusters within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with fewer CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more copy number aberrations and linker histone mutations. This exploratory study shows that stage I FL is genetically heterogeneous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven, whereas BCL2trl- stage III/IV appears to be more BCL6trl driven.

Impact of obstructive sleep apnea on clinical outcomes in patients hospitalized with COVID-19.

PURPOSE: Data from large patient registry studies suggested an increased incidence and increased mortality in coronavirus disease-2019 (COVID-19) in patients with a history of obstructive sleep apnea (OSA). This study aimed to compare the prevalence of OSA in patients with and without COVID-19 among patients admitted to the same hospital in the same time period. In addition, the impact of OSA on clinical outcomes of COVID-19 infection was investigated. METHODS: Observational cohort study. Clinical data were collected retrospectively from the complete medical records for each patient individually from March 1st 2020 to May 16th 2020. RESULTS: A total of 723 patients were diagnosed with COVID-19 and 1161 with non-COVID-19 disease. The prevalence of OSA did not differ between these groups (n = 49; 6.8% versus n = 66; 5.7%; p = 0.230). In patients with COVID-19, mortality was increased in the group of 49 patients with OSA (n = 17; 34.7%) compared to 674 COVID-19 patients without OSA (n = 143; 21.2%; p = 0.028). This increased risk of mortality in COVID-19 patients with OSA (OR = 2.590; 95%CI 1.218-5.507) was independent from Body Mass Index (BMI), male gender, age, diabetes, cardiovascular disease, and obstructive lung disease. Presence of OSA in COVID-19 disease was further associated with an increased length of hospital stay (12.6 ± 15.7 days versus 9.6 ± 9.9 days; p = 0.049). CONCLUSION: The prevalence of OSA did not differ between patients with or without COVID-19, but mortality and hospital length of stay were increased in patients with OSA and comorbid COVID-19. Hence, OSA should be included in COVID-19 risk factor analyses, Clinicians should be aware of the association and the mechanism should be further explored.

Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing.

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

Corrigendum to 'Should treatment of low-level rifampicin mono-resistant tuberculosis be different?' [JCTUBE 23 (2021) 100241].

[This corrects the article DOI: 10.1016/j.jctube.2021.100241.].

Should treatment of low-level rifampicin mono-resistant tuberculosis be different?

BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) was frequently detected in Suriname after the introduction of Xpert MTB/RIF in 2012. Subsequent phenotypic drug-susceptibility testing (DST) was not conclusive at that moment, while RR-TB patients treated with first-line tuberculostatics had good treatment outcome. In our study, we analysed this interesting observation. METHODS: We collected demographic and clinical characteristics and treatment outcome of TB patients from May 2012-December 2018 and performed a univariate and multivariate analysis to assess possible associations with resistance to rifampicin. Secondly, we conducted whole genome sequencing on all available Mycobacterium tuberculosis isolates that had a rifampicin resistance in the Xpert MTB/RIF test and performed phenotypic DST on selected isolates. FINDINGS: RR-TB was detected in 59 (9.6%) patients confirmed by Xpert. These patients were treated with rifampicin-containing regimens in most (88%) of the cases. In all 32 samples examined, a D435Y mutation in the rpoB gene was identified; only one isolate revealed an additional isoniazid mutation. Phenotypic DST indicated low-level rifampicin resistance. In multivariate analysis, the Creole ethnicity was a factor associated with rifampicin resistance (aOR 3.5; 95%CI 1.9-6.4). The treatment success rate for patients with RR-TB (78.0%) was comparable to the treatment outcome in non-RR-TB patients 77.8%. INTERPRETATION: This study confirms a low-level rifampicin mono-resistance in TB patients of Suriname. These patients could benefit from a first-line regimen with high dose rifampicin (or rifabutin), rather than from the lengthy treatment regimens for rifampicin-resistant and multi-drug resistant TB, a concept of stratified medicine also advocated for the treatment of TB. FUNDING: None.

Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare type of T-cell lymphoma that is uniquely caused by a single environmental stimulus. Here, we present a comprehensive genetic analysis of a relatively large series of BIA-ALCL (n = 29), for which genome-wide chromosomal copy number aberrations (CNAs) and mutational profiles for a subset (n = 7) were determined. For comparison, CNAs for anaplastic lymphoma kinase (ALK)- nodal anaplastic large cell lymphomas (ALCLs; n = 24) were obtained. CNAs were detected in 94% of BIA-ALCLs, with losses at chromosome 20q13.13 in 66% of the samples. Loss of 20q13.13 is characteristic of BIA-ALCL compared with other classes of ALCL, such as primary cutaneous ALCL and systemic type ALK+ and ALK- ALCL. Mutational patterns confirm that the interleukin-6-JAK1-STAT3 pathway is deregulated. Although this is commonly observed across various types of T-cell lymphomas, the extent of deregulation is significantly higher in BIA-ALCL, as indicated by phosphorylated STAT3 immunohistochemistry. The characteristic loss of chromosome 20 in BIA-ALCL provides further justification to recognize BIA-ALCL as a separate disease entity. Moreover, CNA analysis may serve as a parameter for future diagnostic assays for women with breast implants to distinguish seroma caused by BIA-ALCL from other causes of seroma accumulation, such as infection or trauma.

The validity and reliability of the exposure index as a metric for estimating the radiation dose to the patient.

INTRODUCTION: With the introduction of digital radiography, the feedback between image quality and over-exposure has been partly lost which in some cases has led to a steady increase in dose. Over the years the introduction of exposure index (EI) has been used to resolve this phenomenon referred to as 'dose creep'. Even though EI is often vendor specific it is always a related of the radiation exposure to the detector. Due to the nature of this relationship EI can also be used as a patient dose indicator, however this is not widely investigated in literature. METHODS: A total of 420 dose-area-product (DAP) and EI measurements were taken whilst varying kVp, mAs and body habitus on two different anthropomorphic phantoms (pelvis and chest). Using linear regression, the correlation between EI and DAP were examined. Additionally, two separate region of interest (ROI) placements/per phantom where examined in order to research any effect on EI. RESULTS: When dividing the data into subsets, a strong correlation between EI and DAP was shown with all R-squared values > 0.987. Comparison between the ROI placements showed a significant difference between EIs for both placements. CONCLUSION: This research shows a clear relationship between EI and radiation dose which is dependent on a wide variety of factors such as ROI placement, body habitus. In addition, pathology and manufacturer specific EI's are likely to be of influence as well. IMPLICATIONS FOR PRACTICE: The combination of DAP and EI might be used as a patient dose indicator. However, the influencing factors as mentioned in the conclusion should be considered and examined before implementation.

Analysis of radiation exposure data from common radiological procedures in Dutch hospitals.

INTRODUCTION: In the Netherlands, Diagnostic Reference Levels (DRLs) have not been based on a national survey as proposed by ICRP. Instead, local exposure data, expert judgment and the international scientific literature were used as sources. This study investigated whether the current DRLs are reasonable for Dutch radiological practice. METHODS: A national project was set up, in which radiography students carried out dose measurements in hospitals supervised by medical physicists. The project ran from 2014 to 2017 and dose values were analysed for a trend over time. In the absence of such a trend, the joint yearly data sets were considered a single data set and were analysed together. In this way the national project mimicked a national survey. RESULTS: For six out of eleven radiological procedures enough data was collected for further analysis. In the first step of the analysis no trend was found over time for any of these procedures. In the second step the joint analysis lead to suggestions for five new DRL values that are far below the current ones. The new DRLs are based on the 75 percentile values of the distributions of all dose data per procedure. CONCLUSION: The results show that the current DRLs are too high for five of the six procedures that have been analysed. For the other five procedures more data needs to be collected. Moreover, the mean weights of the patients are higher than expected. This introduces bias when these are not recorded and the mean weight is assumed to be 77 kg. IMPLICATIONS FOR PRACTICE: The current checking of doses for compliance with the DRLs needs to be changed. Both the procedure (regarding weights) and the values of the DRLs should be updated.