An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.

BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.

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.

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.

CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective.

BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are evaluated with the Apfel score, however patients with low Apfel scores still experience PONV suggesting a genetic predisposition. PONV risk associates with specific M3 muscarinic acetylcholine receptor (CHRM3) rs 2165870 polymorphism. We investigated whether the Apfel score and this genetic variation independently contribute to PONV risk and whether prophylaxis reduces PONV in patients with low Apfel score but at high genetic risk. METHODS: In a prospective, controlled study, 454 subjects undergoing elective surgery were genotyped for rs2165870 and its association with PONV was investigated with log-binomial regression analysis. Subjects were randomised to receive acustimulation/dexamethasone, acustimulation/vehicle, sham acustimulation/dexamethasone, or sham acustimulation/vehicle to investigate their effects on PONV risk. RESULTS: Early PONV occurred in 37% of subjects. The rs2165870 genotype distribution was GG in 191, GA in 207, and AA in 56 subjects. The CHRM3 polymorphism was associated with a relative risk (RR) of 1.5 for GA vs GG [95% confidence interval (CI): 1.1-1.9; P=0.003] and 1.6 for AA vs GG (95% CI: 1.1-2.2; P=0.009) genotypes to develop PONV, and this was independent from the Apfel score (RR per Apfel point: 1.3, 95% CI: 1.2-1.5; P<0.0001). While dexamethasone and acustimulation each reduced the PONV risk by 30% in AA genotype carriers with low Apfel score, combined therapy reduced the risk by 86% (P=0.015). CONCLUSIONS: The CHRM3 polymorphism and the Apfel score independently predict PONV susceptibility. Dexamethasone/acustimulation should be considered in patients with low Apfel score but at high genetic risk. CLINICAL TRIAL REGISTRATION: DRKS00005664.

Validation of the MASK-rhinitis visual analogue scale on smartphone screens to assess allergic rhinitis control.

BACKGROUND: Visual Analogue Scale (VAS) is a validated tool to assess control in allergic rhinitis patients. OBJECTIVE: The aim of this study was to validate the use of VAS in the MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) app (Allergy Diary) on smartphones screens to evaluate allergic rhinitis symptoms and disease control. METHODS: Each user filled 4 different VAS measuring overall, nasal, ocular, and asthma symptoms at least once. Following COSMIN guidelines, we evaluated internal consistency, (Cronbach's alpha coefficient and test-retest), reliability (intraclass correlation coefficients), sensitivity, and acceptability of the MASK-Rhinitis VAS. RESULTS: Between 1 August 2015 and 31 July 2016, the app was used 14 612 times in 15 countries. A total of 1225 users used it more than once, during the evaluated period. The tool resulted to be statistically satisfactory, showing excellent internal consistency (Cronbach's test > 0.84, test-retest > 0.7), reliability (>0.9), and acceptability. In addition, the tool had a good sensitivity when users (n = 521) answered the VAS twice in less than 3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: The MASK-rhinitis VAS is a reliable and valid tool to assess allergic control on smartphone screens, at the population level.

Google Trends terms reporting rhinitis and related topics differ in European countries.

Google Trends (GT) searches trends of specific queries in Google and reflects the real-life epidemiology of allergic rhinitis. We compared Google Trends terms related to allergy and rhinitis in all European Union countries, Norway and Switzerland from 1 January 2011 to 20 December 2016. The aim was to assess whether the same terms could be used to report the seasonal variations of allergic diseases. Using the Google Trend 5-year graph, an annual and clear seasonality of queries was found in all countries apart from Cyprus, Estonia, Latvia, Lithuania and Malta. Different terms were found to demonstrate seasonality depending on the country - namely 'hay fever', 'allergy' and 'pollen' - showing cultural differences. A single set of terms cannot be used across all European countries, but allergy seasonality can be compared across Europe providing the above three terms are used. Using longitudinal data in different countries and multiple terms, we identified an awareness-related spike of searches (December 2016).

Work productivity in rhinitis using cell phones: The MASK pilot study.

Allergic rhinitis often impairs social life and performance. The aim of this cross-sectional study was to use cell phone data to assess the impact on work productivity of uncontrolled rhinitis assessed by visual analogue scale (VAS). A mobile phone app (Allergy Diary, Google Play Store and Apple App Store) collects data from daily visual analogue scales (VAS) for overall allergic symptoms (VAS-global measured), nasal (VAS-nasal), ocular (VAS-ocular) and asthma symptoms (VAS-asthma) as well as work (VAS-work). A combined nasal-ocular score is calculated. The Allergy Diary is available in 21 countries. The app includes the Work Productivity and Activity Impairment Allergic Specific Questionnaire (WPAI:AS) in six EU countries. All consecutive users who completed the VAS-work from 1 June to 31 October 2016 were included in the study. A total of 1136 users filled in 5818 days of VAS-work. Symptoms of allergic rhinitis were controlled (VAS-global <20) in approximately 60% of the days. In users with uncontrolled rhinitis, approximately 90% had some work impairment and over 50% had severe work impairment (VAS-work >50). There was a significant correlation between VAS-global calculated and VAS-work (Rho=0.83, P<0.00001, Spearman's rank test). In 144 users, there was a significant correlation between VAS-work and WPAI:AS (Rho=0.53, P<0.0001). This pilot study provides not only proof-of-concept data on the work impairment collected with the app but also data on the app itself, especially the distribution of responses for the VAS. This supports the interpretation that persons with rhinitis report both the presence and the absence of symptoms.

Pilot study of mobile phone technology in allergic rhinitis in European countries: the MASK-rhinitis study.

BACKGROUND: The use of Apps running on smartphones and tablets profoundly affects medicine. The MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) App (Allergy Diary) assesses allergic rhinitis symptoms, disease control and impact on patients' lives. It is freely available in 20 countries (iOS and Android platforms). AIMS: To assess in a pilot study whether (i) Allergy Diary users were able to properly provide baseline characteristics (ii) simple phenotypic characteristics based upon data captured by the Allergy Diary could be identified and (iii) information gathered by this study could suggest novel research questions. METHODS: The Allergy Diary users were classified into six groups according to the baseline data that they entered into the App: (i) asymptomatic; (ii) nasal symptoms excluding rhinorrhea; (iii) rhinorrhea; (iv) rhinorrhea plus 1-2 nasal/ocular symptoms; (v) rhinorrhea plus ≥3 nasal/ocular symptoms; and (vi) rhinorrhea plus all nasal/ocular symptoms. RESULTS: By 1 June 2016, 3260 users had registered with the Allergy Diary and 2710 had completed the baseline questionnaire. Troublesome symptoms were found mainly in the users with the most symptoms. Around 50% of users with troublesome rhinitis and/or ocular symptoms suffered work impairment. Sleep was impaired by troublesome symptoms and nasal obstruction. CONCLUSIONS: This is the first App (iOS and Android) to have tested for allergic rhinitis and conjunctivitis. A simple questionnaire administered by cell phones enables the identification of phenotypic differences between a priori defined rhinitis groups. The results suggest novel concepts and research questions in allergic rhinitis that may not be identified using classical methods.

Microtubule patterning in the presence of moving motor proteins.

Cytoskeletal polymers such as microtubules (MTs) interact with motor proteins to form higher-order structures. In vitro experiments have shown that MT patterns such as asters, bundles, and vortices can form under the influence of a single type of dynamic motor protein. MTs also can form anti-parallel bundles, similar to bundles that form the mitotic spindle during cell division, under the influence of two types of moving motors with opposite directionality. Despite the importance of MT structures, their mechanism of formation is not yet understood. We develop an integro-partial differential equation model to describe the dynamic interactions between MTs and moving motor proteins. Our model takes into account motor protein speed, processivity, density, and directionality, as well as MT treadmilling and reorganization due to interactions with motors. Simulation results show that plus-end directed motor proteins can form vortex patterns at low motor density, while minus-end directed motor proteins form aster patterns at similar densities. Also, motor proteins with opposite directionality are able to organize MTs into anti-parallel bundles. Our model is able to provide a quantitative and qualitative description of MT patterning, providing insights into possible mechanisms of spindle formation.

Epidemiology of tuberculosis in big cities of the European Union and European Economic Area countries.

This cross-sectional survey aimed to examine the epidemiology of tuberculosis (TB) in European Union (EU) and European Economic Area (EEA) cities with populations greater than 500,000. National TB programme managers were asked to provide data on big city population size, total number of notified TB cases in big cities and national notification rate for 2009. A rate ratio was calculated using the big city TB notification rate as a numerator and country TB notification rate, excluding big city TB cases and population, as a denominator. Twenty of the 30 EU/EEA countries had at least one big city. Pooled rate ratios were 2.5, 1.0, and 0.7 in low-, intermediate- and high-incidence countries respectively. In 15 big cities, all in low-incidence countries, rate ratios were twice the national notification rate. These data illustrate the TB epidemiology transition, a situation whereby TB disease concentrates in big cities as national incidence falls, most likely as a result of the higher concentration of risk groups found there. This situation requires targeted interventions and we recommend that big city TB data, including information about patients' risk factors, are collected and analysed systematically, and that successful interventions are shared.

Extent and origin of resistance to antituberculosis drugs in the Netherlands, 1993 to 2011.

The elimination of tuberculosis (TB) is threatened by an apparent increase in the level of resistance in Mycobacterium tuberculosis. In the Netherlands, where the majority of TB patients are migrants, resistance may also be increasing. We conducted a retrospective study, using 18,294 M. tuberculosis isolates from TB cases notified between 1993 and 2011. We investigated the trends in antituberculosis drug resistance, focusing on the country of birth of the patients and whether resistance had developed during treatment or was the result of transmission of resistant M. tuberculosis strains. For both scenarios, we determined whether this had happened in or outside the Netherlands. Antituberculosis drug resistance was found in 13% of all cases analysed and showed an increasing trend among patients who had been born in the Netherlands (p<0.001) and a decreasing trend among foreign-born (p=0.02) over the study period. Since 2005, the proportion of M. tuberculosis resistant strains among all strains tested has increased in both groups (p=0.03 and p=0.01, respectively). Overall, we found a significantly increasing trend when excluding streptomycin resistance (p<0.001). The trend was most markedly increased for isoniazid resistance (p = 0.01). Although resistance was mainly due to transmission of resistant strains, mostly outside the Netherlands or before 1993 (when DNA fingerprinting was not systematically performed), in some cases (n=45), resistance was acquired in the Netherlands. We conclude that antituberculosis drug resistance is increasing in the Netherlands, mostly related to migration from high TB-incidence countries, but also to domestic acquisition.

Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement.

In low-incidence countries in the European Union (EU), tuberculosis (TB) is concentrated in big cities, especially among certain urban high-risk groups including immigrants from TB high-incidence countries, homeless people, and those with a history of drug and alcohol misuse. Elimination of TB in European big cities requires control measures focused on multiple layers of the urban population. The particular complexities of major EU metropolises, for example high population density and social structure, create specific opportunities for transmission, but also enable targeted TB control interventions, not efficient in the general population, to be effective or cost effective. Lessons can be learnt from across the EU and this consensus statement on TB control in big cities and urban risk groups was prepared by a working group representing various EU big cities, brought together on the initiative of the European Centre for Disease Prevention and Control. The consensus statement describes general and specific social, educational, operational, organisational, legal and monitoring TB control interventions in EU big cities, as well as providing recommendations for big city TB control, based upon a conceptual TB transmission and control model.

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.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways.

In adult male rats, vasopressin (AVP) facilitates social recognition via activation of V1a receptors within the lateral septum. Much less is known about how AVP affects social recognition in adult females or in juvenile animals of either sex. We found that administration of the specific V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP into the lateral septum of adult rats impaired, whereas AVP extended, social discrimination in both sexes. In juveniles, however, we detected a sex difference, such that males but not females showed social discrimination. Interestingly, administration of the V1a receptor antagonist to juveniles (either intracerebroventricularly or locally in the lateral septum) did not prevent social discrimination, but instead significantly decreased the investigation of a novel as opposed to a familiar animal in both sexes, with stronger effects in males. V1a receptors were found to be abundantly expressed in the lateral septum with higher binding density in females than in males. These findings demonstrate that activation of V1a receptors in the lateral septum is important for social recognition in both sexes, and that the roles of septal V1a receptors in social recognition change during development.