The Swiss Systemic lupus erythematosus Cohort Study (SSCS) - cross-sectional analysis of clinical characteristics and treatments across different medical disciplines in Switzerland.

OBJECTIVES: To describe disease characteristics and treatment modalities in a multidisciplinary cohort of systemic lupus erythematosus (SLE) patients in Switzerland. METHODS: Cross-sectional analysis of 255 patients included in the Swiss SLE Cohort and coming from centres specialised in Clinical Immunology, Internal Medicine, Nephrology and Rheumatology. Clinical data were collected with a standardised form. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), an integer physician's global assessment score (PGA) ranging from 0 (inactive) to 3 (very active disease) and the erythrocyte sedimentation rate (ESR). The relationship between SLE treatment and activity was assessed by propensity score methods using a mixed-effect logistic regression with a random effect on the contributing centre. RESULTS: Of the 255 patients, 82% were women and 82% were of European ancestry. The mean age at enrolment was 44.8 years and the median SLE duration was 5.2 years. Patients from Rheumatology had a significantly later disease onset. Renal disease was reported in 44% of patients. PGA showed active disease in 49% of patients, median SLEDAI was 4 and median ESR was 14 millimetre/first hour. Prescription rates of anti-malarial drugs ranged from 3% by nephrologists to 76% by rheumatologists. Patients regularly using anti-malarial drugs had significantly lower SELENA-SLEDAI scores and ESR values. CONCLUSION: In our cohort, patients in Rheumatology had a significantly later SLE onset than those in Nephrology. Anti-malarial drugs were mostly prescribed by rheumatologists and internists and less frequently by nephrologists, and appeared to be associated with less active SLE.

Genome-wide association analysis identifies 20 loci that influence adult height.

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

La recherche au sein des hautes écoles spécialisées 2012: descriptions, analyses, conclusions

Résumé Contexte et objectifs Les activités de recherche appliquée et développement (Ra&D) font partie du mandat de prestations des hautes écoles spécialisées (HES) prescrit par la loi. Néanmoins la tradition, le type et l'importance de la recherche varient fortement en fonction des domaines d'études. Il en va de même pour les liens avec les autres domaines de prestations que sont l'enseignement, la formation continue et les prestations de services. Les activités de Ra&D dans chaque HES s'inscrivent dans la tension entre l'orientation pratique (qui signifie le plus souvent une orientation vers le marché économique) et l'orientation vers la science (signe de leur rattachement au système scientifique). Il en découle des conflits d'intérêts entre les critères de qualité du « succès sur le marché » et de la « réputation scientifique ». En 2005, sur mandat de la Commission pour la technologie et l'innovation (CTI), B. Lepori et L. Attar (2006) ont mené une étude visant à examiner plus particulièrement les stratégies de recherche et l'organisation de la recherche au sein des hautes écoles spécialisées. Aujourd'hui, six ans plus tard, la phase de mise sur pied est en grande partie terminée. En lançant une nouvelle étude, l'Office fédéral de la formation professionnelle et de la technologie (OFFT) et la Commission fédérale des hautes écoles spécialisées (CFHES) souhaitaient faire le point sur les activités de recherche des HES, c'està- dire examiner les résultats des stratégies et de l'organisation de cette phase. Cette étude s'articule principalement autour de l'état actuel de la recherche, de ses problèmes et de ses perspectives. Structure de l'étude La recherche dans les HES se caractérise par différents facteurs d'influence (cultures disciplinaires, traditions, ancrage dans les régions linguistiques, structures organisationnelles, gouvernance, stratégies de positionnement, personnel, etc.). Dans la présente étude, ces facteurs sont systématiquement examinés selon deux dimensions: le « domaine d'études » et la « haute école spécialisée». L'analyse repose notamment sur l'exploitation de documents et de données. Mais cette étude se fonde principalement sur les entretiens menés avec les représentants des HES à différents niveaux de responsabilités. Les hautes écoles spécialisées (HES) Les entretiens avec les directions des HES ainsi que l'exploitation des données et des documents mettent en évidence la grande diversité des sept HES suisses de droit public dans leur structure, leurs combinaisons de domaines d'études et leurs orientations. Les modes de financement de la recherche varient fortement entre les HES. Concrètement, les sources de financement ne sont pas les mêmes d'une HES à l'autre (contributions des organes responsables, fonds de tiers, etc.). Les degrés et formes du pilotage concernant les contenus de la recherche diffèrent également dans une large mesure (définition de pôles de recherche, soutien cumulatif à l'acquisition de fonds de tiers), de même que les stratégies en matière de recrutement et d'encouragement du personnel. La politique de chaque HES implique des tensions et des problèmes spécifiques. Les domaines d'études Sur les dix domaines d'études, quatre ont été choisis à titre d'exemples pour des études approfondies : Technique et technologies de l'information (TI), Economie et services, Travail social, Musique, arts de la scène et autres arts. Chaque domaine d'études a été examiné à chaque fois dans deux HES. Cette méthode permet de relever les différences et les similitudes. Les résultats confirment qu'il existe des différences importantes à bien des égards entre les domaines d'études évalués. Ces différences concernent la position dans le système des hautes écoles, le volume des activités de recherche, l'importance de la recherche au sein des HES, la tradition, l'identité et l'orientation. Elles se retrouvent par ailleurs dans les buts et la place de la Ra&D dans les domaines d'études concernés. Il ressort toutefois qu'il n'y a pas lieu de parler d'une dichotomie entre les « anciens » et les « nouveaux » domaines d'études : Technique, économie et design (TED) d'une part et Santé, social et arts (SSA) d'autre part. Il semble plus pertinent de désigner le domaine d'études 4/144 Technique et TI comme le domaine dominant auquel se référent le pilotage et le financement des HES, que ce soit implicitement ou explicitement. Cadre homogène et espaces hétérogènes Le pilotage et le financement de la Ra&D au sein des hautes écoles spécialisées s'inscrivent dans un modèle-cadre fixé à l'échelle fédérale et principalement axé sur le domaine d'études Technique. Ce modèle-cadre se caractérise par un apport élevé de fonds de tiers (notamment les subventions de la CTI et les fonds privés) et des incitations en faveur de ce mode de financement, par une orientation vers le marché et par un haut degré d'autonomie des établissements partenaires/départements et instituts. Par comparaison avec les hautes écoles universitaires, les HES affichent notamment un faible niveau de financement de base dans le secteur Ra&D. Cet état de fait est certes compatible avec la forme actuelle du financement par la CTI, mais pas avec les règles de financement du Fonds national suisse (FNS). Un financement principalement basé sur les fonds de tiers signifie par ailleurs que l'orientation du contenu de la recherche et la définition de critères de qualité sont confiées à des instances externes, notamment aux mandants et aux institutions d'encouragement de la recherche. Il apparaît en dernier lieu qu'un tel modèle-cadre ne favorise pas les politiques visant à la constitution de pôles de recherche, l'obtention d'une taille critique, et la mise en place d'une coordination. Ces résultats concernent tous les domaines d'études sans avoir pour autant les mêmes conséquences : les domaines d'études se prêtant dans une faible mesure à l'acquisition de fonds de tiers sur des marchés économiques (dans cette étude, il s'agit essentiellement de la Musique, arts de la scène et autres arts, mais également du Travail social dans certains cas) ont plus de difficultés à répondre aux attentes énoncées en termes de succès et de profit. Les HES modifient plus ou moins le modèle-cadre en élaborant elles-mêmes des modèles d'organisation qui prennent en compte leur combinaison de domaines d'études et soutiennent leurs propres orientations et positionnements stratégiques. La combinaison de domaines d'études hétérogènes et de politiques différentes au sein des HES se traduit par une complexité du système des HES, beaucoup plus importante que ce que généralement supposée. De plus, au regard des connaissances lacunaires sur les structures « réelles » de gouvernance des HES, il n'est quasiment pas possible de comparer directement les hautes écoles spécialisées entre elles. Conclusions et recommandations Le principal constat qui ressort d'un ensemble de conclusions et de recommandations des auteurs est que le secteur Ra&D dans les HES doit être plus explicitement évalué en fonction des spécificités des domaines d'études, à savoir du rôle de la recherche pour l'économie et la société, des différences entre les marchés (économiques) correspondants et de l'importance de la Ra&D pour les objectifs visés. L'étude montre clairement qu'il n'y a pas à proprement parler une seule et unique recherche au sein des hautes écoles spécialisées et que la notion de « recherche appliquée » ne suffit ni comme description ni, par conséquence, comme critère d'identité commun. Partant de ce constat, nous recommandons de revoir le mode de financement de la recherche dans les HES et d'approfondir le débat sur les structures de gouvernance sur l'orientation de la Ra&D (et notamment sur les critères de qualité appliqués), de même que sur l'autonomie et la coordination. Les recommandations constituent des points de discussion et n'engagent aucunement l'OFFT ou la CFHES.

Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

An algebraic operator approach to the analysis of Gerber-Shiu functions

We introduce an algebraic operator framework to study discounted penalty functions in renewal risk models. For inter-arrival and claim size distributions with rational Laplace transform, the usual integral equation is transformed into a boundary value problem, which is solved by symbolic techniques. The factorization of the differential operator can be lifted to the level of boundary value problems, amounting to iteratively solving first-order problems. This leads to an explicit expression for the Gerber-Shiu function in terms of the penalty function.

Advantages of digital holographic microscopy for real-time full field absolute phase imaging

Different interferometric techniques were developed last decade to obtain full field, quantitative, and absolute phase imaging, such as phase-shifting, Fourier phase microscopy, Hilbert phase microscopy or digital holographic microscopy (DHM). Although, these techniques are very similar, DHM combines several advantages. In contrast, to phase shifting, DHM is indeed capable of single-shot hologram recording allowing a real-time absolute phase imaging. On the other hand, unlike to Fourier phase or Hilbert phase microscopy, DHM does not require to record in focus images of the specimen on the digital detector (CCD or CMOS camera), because a numerical focalization adjustment can be performed by a numerical wavefront propagation. Consequently, the depth of view of high NA microscope objectives is numerically extended. For example, two different biological cells, floating at different depths in a liquid, can be focalized numerically from the same digital hologram. Moreover, the numerical propagation associated to digital optics and automatic fitting procedures, permits vibrations insensitive full- field phase imaging and the complete compensation for a priori any image distortion or/and phase aberrations introduced for example by imperfections of holders or perfusion chamber. Examples of real-time full-field phase images of biological cells have been demonstrated. ©2008 COPYRIGHT SPIE

Variants in MTNR1B influence fasting glucose levels.

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

Missed appointments in an adolescent outpatient clinic: descriptive analyses of consultations over 8 years.

Missed appointments represent an important medical and economical issue. Few studies on the subject are reported in the literature, particularly regarding adolescents. Our aim was to characterize missed and cancelled appointments in a multidisciplinary outpatient clinic for adolescents, to assess the effectiveness of a policy aimed at reducing missed appointments by introducing payment for those missed appointments not cancelled in advance, and to compare the rates between staff and resident physicians. A total of 32,816 consultations (representing 35 patients aged 12-20 years, 82.4% females) between 1999 and 200 were analysed. The missed appointment rate was 11.8% whilst another 10.9% were cancellations. Females cancelled more than males (11.3% vs. 8.4%, AOR 1.31, 99% CI 1.08-1.59), but there was no difference for missed appointments (11.6% vs. 12.3%, AOR 0.88, 99% CI 0.61-1.08). April and June to October (vacation months) were associated with more missed appointments. Globally mornings had higher rates of missed appointments than afternoons (13.6% vs. 11.2%, AOR 1.25, 99% CI 1.11-1.40). There was a slight difference in missed appointment rates between staff physicians and residents (10.4%; 11.8%, AOR 1.20, 99% CI 1.08-1.33). Missed appointment rates before and after the new policy on missed appointments were similar (1999-2003: 11.9%; 2004-2006: 11.6%, AOR 0.96, 99% CI 0.83-1.10). Conversely, cancellation rates increased from 8.4% (1999-2003) to 14.5% (2004-2006) (AOR 1.83, 99% CI 1.63-2.05). Attendance rates among adolescents show variations depending on vacation and school hours. Being attentive to these factors could help prevent missed appointments. Although having to pay for missed appointments does not increase attendance, it increases cancellations with the advantage that the appointment can be rescheduled.

Décider

Les acteurs du système judiciaire prennent des décisions à des niveaux différents. La distribution des rôles et des responsabilités se définissent par des procédures et des formes d'organisations qui varient parfois fortement d'une juridiction à l'autre. Ainsi, selon le contexte particulier et la nature de la tâche, le forensicien peut par exemple décider lui-même de cibler la recherche d'indices sur des lieux ou d'effectuer des traitements particuliers sur une trace. Il est susceptible dans d'autres rôles de recommander des pistes d'enquête ou d'évaluer la valeur probante d'un indice au profit d'une autorité judiciaire qui prend les décisions de condamnation. De mauvais choix peuvent aboutir in fine à des erreurs judiciaires. Comme les décisions se prennent sur la base d'informations incertaines et incomplètes, les risques d'erreurs doivent s'évaluer dans des cadres formels bien maîtrisés. L'erreur "acceptable" devient ainsi un thème crucial, surtout lorsque les systèmes automatisés sont susceptibles de prendre certaines décisions, notamment dans le cadre du contrôle de l'identité.

Functional and structural basis for a bacteriophage homolog of human RAD52.

In eukaryotes, homologous recombination proteins such as RAD51 and RAD52 play crucial roles in DNA repair and genome stability. Human RAD52 is a member of a large single-strand annealing protein (SSAP) family [1] and stimulates Rad51-dependent recombination [2, 3]. In prokaryotes and phages, it has been difficult to establish the presence of RAD52 homologs with conserved sequences. Putative SSAPs were recently found in several phages that infect strains of Lactococcus lactis[4]. One of these SSAPs was identified as Sak and was found in the virulent L. lactis phage ul36, which belongs to the Siphoviridae family [4, 5]. In this study, we show that Sak is homologous to the N terminus of human RAD52. Purified Sak binds single-stranded DNA (ssDNA) preferentially over double-stranded DNA (dsDNA) and promotes the renaturation of long complementary ssDNAs. Sak also binds RecA and stimulates homologous recombination reactions. Mutations shown to modulate RAD52 DNA binding [6] affect Sak similarly. Remarkably, electron-microscopic reconstruction of Sak reveals an undecameric (11) subunit ring, similar to the crystal structure of the N-terminal fragment of human RAD52 [7, 8]. For the first time, we propose a viral homolog of RAD52 at the amino acid, phylogenic, functional, and structural levels.

Missing value imputation in longitudinal measures of alcohol consumption

Attrition in longitudinal studies can lead to biased results. The study is motivated by the unexpected observation that alcohol consumption decreased despite increased availability, which may be due to sample attrition of heavy drinkers. Several imputation methods have been proposed, but rarely compared in longitudinal studies of alcohol consumption. The imputation of consumption level measurements is computationally particularly challenging due to alcohol consumption being a semi-continuous variable (dichotomous drinking status and continuous volume among drinkers), and the non-normality of data in the continuous part. Data come from a longitudinal study in Denmark with four waves (2003-2006) and 1771 individuals at baseline. Five techniques for missing data are compared: Last value carried forward (LVCF) was used as a single, and Hotdeck, Heckman modelling, multivariate imputation by chained equations (MICE), and a Bayesian approach as multiple imputation methods. Predictive mean matching was used to account for non-normality, where instead of imputing regression estimates, "real" observed values from similar cases are imputed. Methods were also compared by means of a simulated dataset. The simulation showed that the Bayesian approach yielded the most unbiased estimates for imputation. The finding of no increase in consumption levels despite a higher availability remained unaltered. Copyright (C) 2011 John Wiley & Sons, Ltd.

Cysteine-rich Domain 1 of CD40 Mediates Receptor Self-assembly.

The activation of CD40 on B cells, macrophages, and dendritic cells by its ligand CD154 (CD40L) is essential for the development of humoral and cellular immune responses. CD40L and other TNF superfamily ligands are noncovalent homotrimers, but the form under which CD40 exists in the absence of ligand remains to be elucidated. Here, we show that both cell surface-expressed and soluble CD40 self-assemble, most probably as noncovalent dimers. The cysteine-rich domain 1 (CRD1) of CD40 participated to dimerization and was also required for efficient receptor expression. Modelization of a CD40 dimer allowed the identification of lysine 29 in CRD1, whose mutation decreased CD40 self-interaction without affecting expression or response to ligand. When expressed alone, recombinant CD40-CRD1 bound CD40 with a KD of 0.6 μm. This molecule triggered expression of maturation markers on human dendritic cells and potentiated CD40L activity. These results suggest that CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state.

Fast subplasma membrane Ca2+ transients control exo-endocytosis of synaptic-like microvesicles in astrocytes

Astrocytes are the most abundant glial cell type in the brain. Although not apposite for long-range rapid electrical communication, astrocytes share with neurons the capacity of chemical signaling via Ca(2+)-dependent transmitter exocytosis. Despite this recent finding, little is known about the specific properties of regulated secretion and vesicle recycling in astrocytes. Important differences may exist with the neuronal exocytosis, starting from the fact that stimulus-secretion coupling in astrocytes is voltage independent, mediated by G-protein-coupled receptors and the release of Ca(2+) from internal stores. Elucidating the spatiotemporal properties of astrocytic exo-endocytosis is, therefore, of primary importance for understanding the mode of communication of these cells and their role in brain signaling. We here take advantage of fluorescent tools recently developed for studying recycling of glutamatergic vesicles at synapses (Voglmaier et al., 2006; Balaji and Ryan, 2007); we combine epifluorescence and total internal reflection fluorescence imaging to investigate with unprecedented temporal and spatial resolution, the stimulus-secretion coupling underlying exo-endocytosis of glutamatergic synaptic-like microvesicles (SLMVs) in astrocytes. Our main findings indicate that (1) exo-endocytosis in astrocytes proceeds with a time course on the millisecond time scale (tau(exocytosis) = 0.24 +/- 0.017 s; tau(endocytosis) = 0.26 +/- 0.03 s) and (2) exocytosis is controlled by local Ca(2+) microdomains. We identified submicrometer cytosolic compartments delimited by endoplasmic reticulum tubuli reaching beneath the plasma membrane and containing SLMVs at which fast (time-to-peak, approximately 50 ms) Ca(2+) events occurred in precise spatial-temporal correlation with exocytic fusion events. Overall, the above characteristics of transmitter exocytosis from astrocytes support a role of this process in fast synaptic modulation.

Safety and feasibility of NeuroFlo use in eight- to 24-hour ischemic stroke patients.

BACKGROUND: Acute treatment of ischemic stroke patients presenting more than eight-hours after symptom onset remains limited and largely unproven. Partial aortic occlusion using the NeuroFlo catheter can augment cerebral perfusion in animals. We investigated the safety and feasibility of employing this novel catheter to treat ischemic stroke patients eight-hours to 24 h following symptom onset. METHODS: A multicenter, single-arm trial enrolled ischemic stroke patients at nine international academic medical centers. Eligibility included age 18-85 years old, National Institutes of Health stroke scale (NIHSS) score between four and 20, within eight-hours to 24 h after symptom onset, and perfusion-diffusion mismatch confirmed by magnetic resonance imaging. The primary outcome was all adverse events occurring from baseline to 30 days posttreatment. Secondary outcomes included stroke severity on neurological indices through 90 days. This study is registered with ClinicalTrials.gov, number NCT00436592. RESULTS: A total of 26 patients were enrolled. Of these, 25 received treatment (one excluded due to aortic morphology); five (20%) died. Favorable neurological outcome at 90 days (modified Rankin score 0-2 vs. 3-6) was associated with lower baseline NIHSS (P < 0·001) and with longer duration from symptom discovery to treatment. There were no symptomatic intracranial hemorrhages or parenchymal hematomas. Asymptomatic intracranial hemorrhage was visible on computed tomography in 32% and only on microbleed in another 20%. CONCLUSIONS: Partial aortic occlusion using the NeuroFlo catheter, a novel collateral therapeutic strategy, appears safe and feasible in stroke patients eight-hours to 24 h after symptom onset.

Contact tracing investigation after professional exposure to tuberculosis in a Swiss hospital using both tuberculin skin test and IGRA.

SETTING: A 950 bed teaching hospital in Switzerland. AIM: To describe the result of a contact investigation among health care workers (HCW) and patients after exposure to a physician with smear-positive pulmonary tuberculosis in a hospital setting using standard tuberculin skin tests (TST) and Interferon-gamma release assay (IGRA). METHOD: HCW with a negative or unknown TST at hiring had a TST two weeks after the last contact with the index case (T0), repeated six weeks later if negative (T6). All exposed HCW had a T-SPOT.TB at T0 and T6. Exposed patients had a TST six weeks after the last contact, and a T-SPOT.TB if the TST was positive. RESULTS: Among 101 HCW, 17/73 (22%) had a positive TST at T0. TST was repeated in 50 at T6 and converted from negative to positive in eight (16%). Twelve HCW had a positive T-SPOT.TB at T0 and ten converted from negative to positive at T6. Seven HCW with a positive T-SPOT.TB reverted to negative at T6 or at later controls, most of them with test values close to the cut-off. Among 27 exposed patients tested at six weeks, ten had a positive TST, five of them confirmed by a positive T-SPOT.TB. CONCLUSIONS: HCW tested twice after exposure to a case of smear-positive pulmonary TB demonstrated a possible conversion in 10% with T-SPOT and 16% with TST. Some T-SPOT.TB reverted from positive to negative during the follow-up, mostly tests with a value close to the cut-off. Due to the variability of the test results, it seems advisable to repeat the test with values close to the cut-off before diagnosing the presence of a tuberculous infection.