Using longitudinally sampled viral nucleotide sequences to characterize the drivers of HIV-1 transmission.

OBJECTIVES: Understanding the drivers of HIV-1 transmission is of importance for curbing the ongoing epidemic. Phylogenetic methods based on single viral sequences allow us to assess whether two individuals are part of the same viral outbreak, but cannot on their own assess who potentially transmitted the virus. We developed and assessed a molecular epidemiology method with the main aim to screen cohort studies for and to characterize individuals who are 'potential HIV-1 transmitters', in order to understand the drivers of HIV-1 transmission. METHODS: We developed and validated a molecular epidemiology approach using longitudinally sampled viral Sanger sequences to characterize potential HIV-1 transmitters in the Swiss HIV Cohort Study. RESULTS: Our method was able to identify 279 potential HIV-1 transmitters and allowed us to determine the main epidemiological and virological drivers of transmission. We found that the directionality of transmission was consistent with infection times for 72.9% of 85 potential HIV-1 transmissions with accurate infection date estimates. Being a potential HIV-1 transmitter was associated with risk factors including viral load [adjusted odds ratiomultivariable (95% confidence interval): 1.86 (1.49-2.32)], syphilis coinfection [1.52 (1.06-2.19)], and recreational drug use [1.45 (1.06-1.98)]. By contrast for the potential HIV-1 recipients, this association was weaker or even absent [1.18 (0.82-1.72), 0.89 (0.52-1.55) and 1.53 (0.98-2.39), respectively], indicating that inferred directionality of transmission is useful at the population level. CONCLUSIONS: Our results indicate that longitudinally sampled Sanger sequences do not provide sufficient information to identify transmitters with high certainty at the individual level, but that they allow the drivers of transmission at the population level to be characterized.

Recombinant HIV-1 vaccine candidates based on replication-defective flavivirus vector.

Multiple approaches utilizing viral and DNA vectors have shown promise in the development of an effective vaccine against HIV. In this study, an alternative replication-defective flavivirus vector, RepliVax (RV), was evaluated for the delivery of HIV-1 immunogens. Recombinant RV-HIV viruses were engineered to stably express clade C virus Gag and Env (gp120TM) proteins and propagated in Vero helper cells. RV-based vectors enabled efficient expression and correct maturation of Gag and gp120TM proteins, were apathogenic in a sensitive suckling mouse neurovirulence test, and were similar in immunogenicity to recombinant poxvirus NYVAC-HIV vectors in homologous or heterologous prime-boost combinations in mice. In a pilot NHP study, immunogenicity of RV-HIV viruses used as a prime or boost for DNA or NYVAC candidates was compared to a DNA prime/NYVAC boost benchmark scheme when administered together with adjuvanted gp120 protein. Similar neutralizing antibody titers, binding IgG titers measured against a broad panel of Env and Gag antigens, and ADCC responses were observed in the groups throughout the course of the study, and T cell responses were elicited. The entire data demonstrate that RV vectors have the potential as novel HIV-1 vaccine components for use in combination with other promising candidates to develop new effective vaccination strategies.

Quantifying the drivers of HIV transmission and prevention in men who have sex with men: a population model-based analysis in Switzerland.

OBJECTIVES: Despite the huge success of antiretroviral therapy (ART), there is an ongoing HIV epidemic among men who have sex with men (MSM) in resource-rich countries. Understanding the driving factors underlying this process is important for curbing the epidemic. METHODS: We simulated the HIV epidemic in MSM in Switzerland by stratifying a mathematical model by CD4 count, the care cascade and condom use. The model was parametrised with clinical, epidemiological and behavioural data from the Swiss HIV Cohort Study and surveys in the HIV-negative population. RESULTS: According to our model, 3.4% of the cases that would otherwise have occurred in 2008-2015 were prevented by early initiation of ART. Only 0.6% of the cases were attributable to a change in condom use in the HIV-positive population, as less usage is mainly seen in virally suppressed MSM. Most new infections were attributable to transmission from recently infected undiagnosed individuals. It was estimated that doubling the diagnosis rate would have resulted in 11.8% fewer cases in 2001-2015. Moreover, it was estimated that introducing pre-exposure prophylaxis (PrEP) for 50% of those MSM not using condoms with occasional partners would have resulted in 22.6% fewer cases in 2012-2015. CONCLUSIONS: By combining observational data on the relevant epidemiological and clinical processes with a mathematical model, we showed that the 'test and treat' approach is most effective in reducing the number of new cases. Only a moderate population-level effect was estimated for early initiation of ART and a weak effect for the change in condom use of diagnosed MSM. Protecting HIV-negative individuals who are not using condoms with PrEP was shown to have a major impact.

Positive and negative regulation of cellular immune responses in physiologic conditions and diseases.

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

[Patellar position and lateral approach for total knee arthroplasty in degenerative knees with lateral femoropatellar arthrosis]. / Positionnement patellaire et voie latérale dans l'arthroplastie totale pour gonarthrose avec arthrose fémoro-patellaire latéralisée: comparaison radiologique avec la voie médiale.

PURPOSE OF THE STUDY: Patellar malposition is a well-recognized patellar complication after total knee arthroplasty. Such residual malposition is particularly frequent when the knee presents lateral femoropatellar arthrosis. We compared the radiological position of the patella after total knee arthroplasty in degenerative knees with lateral femoropatellar arthrosis performed via a medial or lateral approach with elevation of the anterior tibial tuberosity. MATERIAL AND METHODS: Twenty-six total knee arthroplasties were reviewed retrospectively. Thirteen prostheses had been inserted via a medial approach and thirteen via a lateral approach. A posterior stabilized implant was used with an original technique for insertion of the patellar implant. The only difference between the groups was the approach. In the "lateral" group, the lateral approach was used to raise the tibial tuberosity and perform lateral marginal patellectomy. The tibial tuberosity was reinserted in all cases without transposition. Preoperative and 3-month postoperative radiographs (weight-bearing, AP, lateral, femoropatellar 30 degrees flexion) were reviewed. Preoperative patellar displacement was at least 5 mm. There was no difference between the two groups for age, gender, weight, height, joint motion, pre- and postoperative mechanical alignment (HKA), or preoperative patellar gliding (7.6 mm in the "medial" group and 9.7 mm in the "lateral" group). RESULTS: Recurrent patellar dislocation occurred in one patient in the "medial" group and one patient in the "lateral" group had an anterior impaction of the tibial plateau following a fall. Patellar gliding was corrected in both groups: 0.7 +/- 1.8 mm in the "medial group" and 0.0 +/- 0 in the lateral group (p > 0.05). Residual patellar tilt was +4.2 +/- 3 degrees in the medial group (lateral tilt) and -3.3 +/- 5.4 degrees in the lateral group (medial tilt) (p = 0.003). DISCUSSION: Pateller gliding was corrected irrespective of the approach. Conversely, the medial approach did not allow effective correction of patellar tilt. The lateral approach with elevation of the anterior tibial tuberosity did not increase morbidity compared with the medial approach. It enabled avoiding residual lateral patellar tilt which can be a source of patellar complications. We prefer this approach for arthroplasty on degenerated knees with lateral femoropatellar arthrosis.

Were micrometeorites a source of prebiotic molecules on the early Earth?

"Interplanetary Dust Particles" with sizes approximately 10 micrometers collected in the stratosphere (IDPs), as well as much larger "giant" micrometeorites retrieved from Antarctic ice melt water (AMMs), are mostly composed of unequilibrated assemblages of minerals, thus being related to primitive unequilibrated meteorites. Two independent evaluations of the mass flux of micrometeorites measuring approximately 50 micrometers to approximately 200 micrometers, recovered from either the Greenland or the Antarctic ice sheets have been reported (approximately 20,000 tons/a). A comparison with recent evaluation of the flux of meteorites reaching the Earth's surface (up to masses of 10,000 tons), indicates that micrometeorites represent about 99.5% of the extraterrestrial material falling on the Earth's surface each year. As they show carbon concentrations exceeding that of the most C-rich meteorite (Orgueil), they are the major contributors of extraterrestrial C-rich matter accreting to the Earth today. Moreover they are complex microstructured aggregates of grains. They contain not only a variety of C-rich matter, such as a new "dirty" magnetite phase enriched in P, S, and minor elements, but also a diversity of potential catalysts (hydrous silicates, oxides, sulfides and metal grains of Fe/Ni composition, etc.). They could have individually functioned on the early Earth, as "micro-chondritic-reactors" for the processing of prebiotic organic molecules in liquid water. Future progress requires the challenging development of meaningful laboratory simulation experiments, and a better understanding of the partial reprocessing of micrometeorites in the atmosphere.

[Gluteal posterior approach for surgery of the acetabulum]. / La voie circumfessiere pour abord posterieur du cotyle.

PURPOSE OF THE STUDY: This approach was developed to avoid gluteus maximus muscle injury which is divided when using the common Langenbeck-Kocher approach. The posterior perigluteal approach also provides better visualization of the posterior aspect of the acetabulum. MATERIAL AND METHODS: A semi-circular incision is made from the fascia lata at the anterior aspect of the greater trochanter and then directed to the posterio-superior iliac spine. The gluteus maxirnus is then simply retracted medially with blunt retractors. Sixty eight acetabular fractures have been operated with this approach including both mixed and complex fractures of the posterior column. Occasionally fractures of both columns have been operated in two procedures, one posterior and then a second anterior approach. RESULTS: The posterior perigluteal approach preserves gluteus maximus muscle tone. It seems to avoid post-operative ossification. CONCLUSION: We propose an approach which, compare to the Langenbeck- Kocher approach, is less traumatic, and as easy to perform.

[Septic osteoarthritis of the hip with acetabular involvement in children. Value of x-ray computed tomography]. / Ostéoarthrite septique de hanche avec atteinte acétabulaire chez le grand enfant. Intérêt de la tomodensitométrie.

The authors reported a case of osteomyelitis of the acetabulum associated with a septic hip arthritis in an eight year old child. They confirmed the difficulties of the diagnosis of this rare disease, and they pointed out the importance of tomographic scan (CT scan).

[Functional treatment of recent fractures of the humeral shaft using the Sarmiento method]. / Traitement fonctionnel des fractures récentes de la diaphyse humérale par la méthode de Sarmiento.

Functional treatment of humeral shaft recent fractures by A. Sarmiento's method was described in 1977. It is based on fixation with a plaster or plastic sleeve individually molded. This sleeve keeps free the adjacent joints, allowing an early functional rehabilitation and a fast consolidation. A 50 cases serial study from 1983 to 1987, confirms the advantages of a method which allies reasonable means, safety and complete reliability to obtain a good and rapid consolidation (one case of non-union due to a technical failure), and rapidly recovered function. We had frequently resulting axial defects: 16 patients have mal-union with more than 10 degrees of angular deformity but without any functional consequences. The advantage of this method compared to usual orthopaedic, or surgical treatments leads us to propose it to most of our patients.

[Brucella osteitis in children]. / Ostéite à brucelles chez l'enfant.

The authors report a case presenting with a very rare localization of brucellosis: the isolated involvement of a single bone of the metatarsus, in a child in otherwise excellent general condition. The lesions of the diaphysis and epiphyses induced a fragility of the epiphyseal cartilage and a minimal traumatism resulted in a detachment of the epiphysis which was the first clinical sign. The bacteriological examination of a sample of pus led to the early diagnosis of brucellosis, therefore allowing efficient treatment.

[Complex injuries of the upper end of the 2 forearm bones]. / Traumatismes complexes de l'extrémité supérieure des deux os de l'avant-bras.

Thirty-four cases of severe trauma to the proximal ends of both bones of the forearm have been seen. All were treated surgically. A classification is proposed related to the site of the ulnar fracture. Type I is metaphyseal and the displacement is posterior, the reverse of that of a Monteggia fracture, with a posterior dislocation of the superior radio-ulnar joint. Type II is epiphyseal with anterior displacement. The superior radio-ulnar joint is intact. Type III is metaphysio-epiphyseal with anterior displacement. Type IV is the same with posterior displacement. Fractures of the radial head are present in all cases with posterior displacement and in these types, secondary displacements and non-unions are frequent (six cases). These were related to inadequate fixation of the ulna and to resection of the radial head which led to an increased strain on the ulnar fracture. Severe limitation of movements was infrequent (five cases) and was usually seen in fractures with posterior displacement. It was related to the time of cast immobilization and to the fracture of the radial head. Fractures with anterior displacement and an associated fracture of the radial head were rare but had a better prognosis in spite of the intra-articular site of the fracture. The relevance of repair of the radial column is stressed as being as important as stable fixation of the ulnar fracture.