A Randomized Placebo-Controlled Efficacy Study of a Prime Boost Therapeutic Vaccination Strategy in HIV-1-Infected Individuals: VRI02 ANRS 149 LIGHT Phase II Trial.

In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.)IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.

Exogenous acquisition of Pseudomonas aeruginosa in intensive care units: a prospective multi-centre study (DYNAPYO study).

BACKGROUND: Pseudomonas aeruginosa remains one of the most common nosocomial pathogens in intensive care units (ICUs). Although exogenous acquisition has been widely documented in outbreaks, its importance is unclear in non-epidemic situations. AIM: To elucidate the role of exogenous origin of P. aeruginosa in ICU patients. METHODS: A chronological analysis of the acquisition of P. aeruginosa was performed using samples collected in 2009 in the DYNAPYO cohort study, during which patients and tap water were screened weekly. Molecular relatedness of P. aeruginosa isolates was investigated by pulsed-field gel electrophoresis. Exogenous acquisition was defined as identification of a P. aeruginosa pulsotype previously isolated from another patient or tap water in the ICU. FINDINGS: The DYNAPYO cohort included 1808 patients (10,402 samples) and 233 water taps (4946 samples). Typing of 1515 isolates from 373 patients and 375 isolates from 81 tap water samples identified 296 pulsotypes. Analysis showed exogenous acquisition in 170 (45.6%) of 373 patients. The pulsotype identified had previously been isolated from another patient and from a tap water sample for 86 and 29 patients, respectively. The results differed according to the ICU. CONCLUSION: Exogenous acquisition of P. aeruginosa could be prevented in half of patients. The overall findings of this survey support the need for studies on routes of transmission and risk assessment approach to better define how to control exogenous acquisition in ICUs.

Risk factors for colonization and infection by Pseudomonas aeruginosa in patients hospitalized in intensive care units in France.

OBJECTIVE: To assess the role of environment, medical care and individual risks factors for P. aeruginosa colonization and infection. STUDY DESIGN AND SETTING: A French multicentric prospective study involved ten ICUs for a five months period. Every adult patient newly hospitalized in ICUs with no P. aeruginosa carriage up to 48 hours after admission was included and weekly screened before discharge or death. Screening swabs were either rectal, sputum or oropharyngeal samples. Hydric environment was also sampled each week. Data on patient clinical features, environmental and device exposures, and antibiotics supports were regularly collected. Multivariate analysis was performed with a multistate model. RESULTS: The overall prevalence of P. aeruginosa carriage was 15.3% (201/1314). Risk factors associated with patient colonization were: use of inactive antibiotics against P. aeruginosa (HR = 1.60 [1.15-2.21] p<0.01), tap water contamination at the entry in the room (HR = 1.66 [1.01-2.27] p<0.05) and mechanical invasive ventilation (HR = 4.70 [2.66-8.31] p<0.0001). Active antibiotics prevented from colonization (HR = 0.67 [0.48-0.93] p = 0.02) and from infection (HR = 0.64 [0.41-1.01] p = 0.05). Interaction between hydric environment antibiotics support was not statistically associated with patient colonization. CONCLUSION: Hydric contamination and antibiotics pressure seem to remain key independent risk factors in P. aeruginosa colonization. These results advocate the need to carry on preventive and targeted interventions toward healthcare associated infections.

Public Health and Epidemiology Informatics.

Objectives: To summarize current research in the field of Public Health and Epidemiology Informatics. Methods: The complete 2016 literature concerning public health and epidemiology informatics has been searched in PubMed and Web of Science, and the returned references were reviewed by the two section editors to select 14 candidate best papers. These papers were then peer-reviewed by external reviewers to allow the editorial team an enlightened selection of the best papers. Results: Among the 829 references retrieved from PubMed and Web of Science, three were finally selected as best papers. The first one compares Google, Twitter, and Wikipedia as tools for Influenza surveillance. The second paper presents a Geographic Knowledge-Based Model for mapping suitable areas for Rift Valley fever transmission in Eastern Africa. The last paper evaluates the factors associated with the visit of Facebook pages devoted to Public Health Communication. Conclusions: Surveillance is still a productive topic in public health informatics but other very important topics in public health are appearing.

Percutaneous Image-Guided Cryoablation as Second-Line Therapy of Soft-Tissue Venous Vascular Malformations of Extremities: A Prospective Study of Safety and 6-Month Efficacy.

PURPOSE: To report the safety and short-term efficacy of percutaneous image-guided cryoablation performed as second-line therapy of venous vascular malformations (VVM) of extremities. MATERIALS AND METHODS: In this non-blinded, no-randomized trial, cryoablation was proposed in 14 patients presenting with symptomatic VVM for recurrences after treatment. Eligibility criteria were: cryoablation feasible, localization at least 5 mm from skin and nerves, absence of contra-indication for anesthesia. Safety was evaluated by the common terminology criteria for adverse events (AE). Clinical response was assessed by evaluating pain at day 7, month 2 and 6 using visual analog scale; quality of life before cryoablation and at 2 and 6 months after using questionnaire. Evolution of volume was evaluated by MRI at 6 months. Comparison was performed using the Wilcoxon test. RESULTS: A technical success was observed in all cases. While 11 patients (78.6%) presented AE (13 grade 1-2 and 3 grade 3), only two severe AE (grade 3) related to cryoablation occurred in two patients (14.3%) during the 6-month follow-up: one immediate sciatic paralysis and one delayed paresthesia. A clinical response was observed in 12 patients (85.7%) at 6 months. Pain decreased significantly from 42.5 ± 14.2 mm before the intervention to 11.8 ± 17.9 mm at 6 months (P = 0.002). A significant decrease in the mean volume from 12.8 ± 14.3 to 3 ± 2.7 cm3 was observed at 6 months (P = 0.002). CONCLUSION: Percutaneous cryoablation is a promising alternative treatment for sclerotherapy-resistant venous malformations. However, to improve safety, careful patient selection and treatment planning will be mandatory.

Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients.

OBJECTIVES: The aim of this work was to provide a reference for the CD4 T-cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV-1-infected patients. METHODS: All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions. RESULTS: A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/µL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/µL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay 'on track' (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise. CONCLUSIONS: Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.

A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials.

BACKGROUND: Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. PATIENTS AND METHODS: Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. RESULTS: Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. CONCLUSIONS: Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.

Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients.

Massive loss of lamina propria CD4(+) T cells, changes in the lymphatic architecture, and altered intestinal epithelial barrier leading to microbial translocation are the common features of HIV-1 infection and are not fully restored under combined antiretroviral therapy (cART). To better understand determinants of gut mucosal restoration, we have performed phenotypic and gene expression analyses of the gut from HIV-infected patients, naive or treated with cART initiated either at the early phase of the primary infection or later during the chronic phase. We found a depletion of T helper type 22 (Th22) and interleukin-17-producing cells in naive patients. These populations, except Th22 cells, were not restored under cART. Regulatory T cells/Th17 ratio was significantly increased in HIV-infected patients and was inversely correlated to the restoration of CD4(+) T cells but not to gut HIV DNA levels. Gene profile analysis of gut mucosal distinguished two groups of patients, which fitted with the timing of cART initiation. In their majority early, but not later treated patients, exhibited conserved intestinal lymphoid structure, epithelial barrier integrity and dendritic cell maturation pathways. Our data demonstrate that early initiation of cART helps to preserve and/or restore lymphoid gut mucosal homeostasis and provide a rationale for initiating cART during the acute phase of HIV infection.

Risk factors for Pseudomonas aeruginosa acquisition in intensive care units: a prospective multicentre study.

BACKGROUND: Pseudomonas aeruginosa is a major nosocomial pathogen in intensive care units (ICUs); however, endogenous versus exogenous origin of contamination remains unclear. AIM: To identify individual and environmental ICU risk factors for P. aeruginosa acquisition. METHODS: A five-month prospective multicentric study was performed in ten French ICUs. Adult patients hospitalized in ICU for ≥ 24 h were included and screened for P. aeruginosa colonization on admission, weekly and before discharge. P. aeruginosa acquisition was defined by a subsequent colonization or infection if screening swabs on admission were negative. Water samples were obtained weekly on water taps of the ICUs. Data on patient characteristics, invasive devices exposure, antimicrobial therapy, P. aeruginosa water and patient colonization pressures, and ICU characteristics were collected. Hazard ratios (HRs) were estimated using multivariate Cox model. FINDINGS: Among the 1314 patients without P. aeruginosa on admission, 201 (15%) acquired P. aeruginosa during their ICU stay. Individual characteristics significantly associated with P. aeruginosa acquisition were history of previous P. aeruginosa infection or colonization, cumulative duration of mechanical ventilation and cumulative days of antibiotics not active against P. aeruginosa. Environmental risk factors for P. aeruginosa acquisition were cumulative daily ward 'nine equivalents of nursing manpower use score' (NEMS) [hazard ratio (HR): 1.47 for ≥ 30 points; 95% confidence interval (CI): 1.06-2.03] and contaminated tap water in patient's room (HR: 1.76; CI: 1.09-2.84). CONCLUSION: Individual risk factors and environmental factors for which intervention is possible were identified for P. aeruginosa acquisition.

Parameter identification for model of T cell proliferation in lymphopenia conditions.

The number of T Lymphocytes (T cells) in the body is under homeostatic control. At equilibrium, the majority of naive T cells are non-dividing and express low levels of the surface protein CD44. In conditions of T cell deficiency (lymphopenia), naive T cells enter into a proliferative phase, undergoing cell division accompanied by a subtle change in their surface expression of CD44. In this study, we use a mathematical modelling approach to analyse the proliferative response of transgenic T cells in lymphopenic conditions. Our nonlinear model is composed of ordinary differential equations and partial differential equations structured by age (maturity of cell) and CD44 expression. To better understand the evolution of CD44 expression on the surface of T cells during cell division, we present a numerical analysis to solve a parameter identification problem. Finally, we show the parameters and the simulations that we obtain from the model and compare them to experimental data.

Dynamical models of biomarkers and clinical progression for personalized medicine: the HIV context.

Mechanistic models, based on ordinary differential equation systems, can exhibit very good predictive abilities that will be useful to build treatment monitoring strategies. In this review, we present the potential and the limitations of such models for guiding treatment (monitoring and optimizing) in HIV-infected patients. In the context of antiretroviral therapy, several biological processes should be considered in addition to the interaction between viruses and the host immune system: the mechanisms of action of the drugs, their pharmacokinetics and pharmacodynamics, as well as the viral and host characteristics. Another important aspect to take into account is clinical progression, although its implementation in such modelling approaches is not easy. Finally, the control theory and the use of intrinsic properties of mechanistic models make them very relevant for dynamic treatment adaptation. Their implementation would nevertheless require their evaluation through clinical trials.

Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study.

BACKGROUND: The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. METHODS: We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored. RESULTS: Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. CONCLUSIONS: Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. CLINICAL TRIALS REGISTRATION: NCT0047732.

Cerebral blood flow modulation by transcutaneous cranial electrical stimulation with Limoge's current.

OBJECTIVES: Transcutaneous cranial electrical stimulation (TCES) delivers a high-frequency (166 kHz) pulsed biphasic balanced current with a pulse repetition frequency of 100 Hz with 40% duty cycle through a negative electrode and two positive electrodes over the skull. TCES has a proven ability to potentiate anesthesia and analgesia, although the physiological mechanisms of this effect remain unclear. We hypothesized that the mechanism is a modulation of CBF in the central endogenous opioid system. This study aimed at determining the effects of TCES on CBF to elucidate its physiological mechanism. METHODS: Thirty-six healthy volunteers were randomly assigned to active or placebo TCES, and all assessments were double blind. TCES was performed using the Anesthelec™ device. In the stimulated group, an active cable was used, and in the control group (sham), the cable was inactive. CBF was measured by XeCT™ before and after two hours of TCES. RESULTS: Globally, CBF was unchanged by TCES. However, locally, TCES induced a significant CBF decrease in the brainstem and thalamus, which are structures involved in pain and anxiety (TCES and control CBF decrease were 18.5 and 11.9 mL/100g brain tissue/min, respectively). CONCLUSION: TCES can modulate local CBF but it has no effect on overall CBF. [Clinical Trials. gov number: NCT00273663].

Influence of mannose-binding lectin genotypes and serostatus in allo-SCT: analysis of 131 recipients and donors.

Mannan-binding lectin (MBL) deficiency is determined by MBL gene polymorphisms and is associated with an increased infection risk. To clarify the role of MBL in Allo-SCT, 131 recipients-donors were analysed. MBL genotypes were determined by PCR and heteroduplex analyses, MBL serum levels by ELISA, and MBL oligomers by western blotting. MBL levels <400 ng/ml were associated with increased susceptibility to fungal pneumonia (7/12 vs 35/111; P=0.04, adjusted P=0.002), HSV/VZV (7/12 vs 26/111; P=0.03), CMV reactivation and acute GVHD. Donor genotypes had no influence. Pre-SCT MBL levels corresponded to recipients' genotypes (P<0.001), changed significantly post-SCT, but were not influenced by donors' genotypes. MBL oligomer profiles were similar pre-/post-SCT. Cultured CD34+ cells were found not to synthesise MBL. In conclusion, low MBL levels pre-transplant predisposed patients to sepsis, fungal and viral infection. Donors' MBL genotypes did not influence infection rates. Prospective studies should clarify the importance of MBL as a prelude for MBL replacement after SCT.

Prevalence and factors associated with renal impairment in HIV-infected patients, ANRS C03 Aquitaine Cohort, France.

OBJECTIVES: The aims of the present study were to estimate the prevalence of renal impairment (RI) among HIV-infected adult patients and to investigate the associated factors. METHODS: A cross-sectional survey was conducted in a French hospital-based cohort. Clearance of creatinine (CC) was calculated using the Cockcroft-Gault formula. Four stages of RI were defined: mild (60-90 mL/min), moderate (30-60), severe (15-30) and end stage (<15). Logistic regression models were used to investigate factors associated with RI. RESULTS: The male/female ratio of the 2588 patients enrolled was 3:1 and the median age was 42 years. At the time of assessment of CC, the median CD4 count was 430 cells/microL and HIV plasma viral load (VL) was<50 copies/mL in 60%. The overall prevalence of RI was 39.0%: 34.2% mild, 4.4% moderate, 0.3% severe and 0.2% end-stage. Mild RI was associated with female gender [odds ratio (OR)=3.3: 95% CI 2.6-4.3)], age >50 years (OR=9.8: 7.4-13.0) and 40-50 years (OR=1.9: 1.5-2.4), body mass index (BMI) <22 kg/m(2) (OR=3.3: 2.7-4.3) and tenofovir exposure (OR=1.4: 1.0-1.9 for <1 year and OR=1.5: 1.2-2.0 for >1 year). Advanced RI (CC <60 mL/min) was associated with age >50 years (OR=5.6: 2.9-10.9) and 40-50 years (OR=2.2: 1.1-1.4), BMI <22 kg/m(2) (OR=1.5: 1.0-2.4), hypertension (OR=2.5: 1.4-2.5) and indinavir (IDV) exposure >1 year (OR=2.3: 1.5-3.6). CONCLUSION: This survey confirms the high prevalence of RI in HIV-infected patients and indicates the importance of the investigation of renal function especially in women, older patients, those with a low BMI or treated with tenofovir or IDV.

TNFSF15 polymorphisms are associated with susceptibility to inflammatory bowel disease in a new European cohort.

OBJECTIVES: Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. METHODS: A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. RESULTS: The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A. CONCLUSIONS: This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

[Yellow fever vaccination in non-immunocompetent patients]. / Vaccination contre la fièvre jaune en dehors des sujets immunocompétents.

Any person travelling in countries where yellow fever (YF) is endemic and without presenting contra-indication for the vaccination against YF may be vaccinated. This vaccination can very rarely induce a potentially lethal neurotropic or viscerotropic disease. In severely immunodeficient patients, the vaccination is contra-indicated because postvaccinal encephalitis may occur after the vaccination, due to vaccine strain pathogenecity. It is important to evaluate the general health status in elderly individuals before vaccinating because of the increased risk of viscerotropic disease in people of 60 years of age and over. Pregnant women should not be vaccinated, except if departure to an endemic zone is unavoidable. YF vaccinatio is contra-indicated for newborns under six months of age. Solid organ grafts, congenital immunodeficiency, leukemia, lymphoma, cancer, and immunosuppressive treatments are contra-indications for this vaccination. Nevertheless, YF immunization is possible after a bone marrow graft and a two-year period without graft-versus-host disease or immunosuppressive treatment. There is no data to support that immunization of the dono prior to the graft could confer protection against yellow fever to the recipient. Low doses, short courses of corticosteroids either as systemic treatment or intra-articular injections are not contra-indications for YF vaccination. Patients infected with HIV with stable clinical status and T CD4-cel count above 200 cells per millimetre cube may be vaccinated. Thymic diseases, including thymoma and thymectomy, are contra-indications for YF vaccination. Finally, a substantial residual level of antibodies beyond 10 years after the latest vaccination could confer protection, thus avoiding a new vaccination when it is an issue.

When it is better to estimate a slope with only one point.

When investigating the change in a biomarker, it is often believed that at least two measurements are needed from each participant, and that those with only one measurement should be excluded. In this short note, we explain why this could lead to imprecise and biased estimates. Furthermore, we discuss a standard statistical method that handles such issues.