Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Using a Modeling-Based Approach to Assess and Optimize HIV Linkage to Care Services.

Evidence-based linkage to care interventions (LTCs) help recently diagnosed HIV+ individuals engage in care in a timely manner yet are heavily impacted by the systems in which they are embedded. We developed a prototype agent-based model informed by data from an established LTC program targeting youth and young adults aged 13-24 in Memphis, Tennessee. We then tested two interventions to improve LTC in a simulated environment: expanding testing sites versus using current testing sites but improving direct referral to LTC staff from organizations providing testing, to understand the impact on timely linkage to care. Improving direct referral to the LTC program decreased days to successful linkage from an average of 30 to 23 days but expanding testing sites increased average days to 31 days unless those sites also made direct referrals. We demonstrated how LTC is impacted by the system and interventions for shortening days to linkage to care.

[The benefit of systematic hearing screening of school-age children]. / Bénéfice d'un dépistage systématique de la surdité chez l'enfant en âge scolaire.

The hearing is routinely tested in all newborns in most European countries. Thereafter, no hearing test is performed in a systematic way, despite the many conditions that can cause hearing loss in the first years of life. If language acquisition is possible with only one ear, even a unilateral hearing loss can be the cause of learning difficulties at school. In Geneva, a screening program for hearing deficit was introduced in 1955 in all primary schools of the canton. This paper shows the efficiency of the program, which can detect unnoticed deafness, sometimes in children whose neonatal screening had proved normal. Such a program should be applied to all private schools and to schools for disabled children.

Step-gate polysilicon nanowires field effect transistor compatible with CMOS technology for label-free DNA biosensor.

Currently, detection of DNA hybridization using fluorescence-based detection technique requires expensive optical systems and complex bioinformatics tools. Hence, the development of new low cost devices that enable direct and highly sensitive detection stimulates a lot of research efforts. Particularly, devices based on silicon nanowires are emerging as ultrasensitive electrical sensors for the direct detection of biological species thanks to their high surface to volume ratio. In this study, we propose innovative devices using step-gate polycrystalline silicon nanowire FET (poly-Si NW FETs), achieved with simple and low cost fabrication process, and used as ultrasensitive electronic sensor for DNA hybridization. The poly-SiNWs are synthesized using the sidewall spacer formation technique. The detailed fabrication procedure for a step-gate NWFET sensor is described in this paper. No-complementary and complementary DNA sequences were clearly discriminated and detection limit to 1 fM range is observed. This first result using this nano-device is promising for the development of low cost and ultrasensitive polysilicon nanowires based DNA sensors compatible with the CMOS technology.

[Statins and anesthesia: dilemma or obviousness? Is there still room for withdrawal of chronic statin therapy before surgery?]. / Statines et anesthésie: dilemme ou évidence? Faut-il arrêter ou poursuivre le traitement par statines avant une intervention chirurgicale?

Due to their action on the low-density lipoprotein-cholesterol (LDL-Cholesterol), statins efficiently take part in the treatment of coronary artery disease (CAD). Moreover, they exert various effects (called "pleiotropic") independently of their lipid lowering actions. All of these effects interact with inflammation, thrombosis and vasoconstriction during the perioperative period. However, statins may also increase the risk of rhabdomyolysis, a rare but potentially lethal complication. In this article, we will describe the advantages and disadvantages of statin therapy during the perioperative period. Although in the past, withdrawal of statins was recommended before anesthesia, there is now evidence that statins must be continued or even must be introduced before surgery. We will try to identify relevant situations were statins are still under-prescribed before surgery.

Distinct regulation of stearoyl-CoA desaturase 1 gene expression by cis and trans C18:1 fatty acids in human aortic smooth muscle cells.

Consumption of trans fatty acids is positively correlated with cardiovascular diseases and with atherogenic risk factors. Trans fatty acids might play their atherogenic effects through lipid metabolism alteration of vascular cells. Accumulation of lipids in vascular smooth muscle cells is a feature of atherosclerosis and a consequence of lipid metabolism alteration. Stearoyl-CoA desaturase 1 (scd1) catalyses the production of monounsaturated fatty acids (e.g. oleic acid) and its expression is associated with lipogenesis induction and with atherosclerosis development. We were interested in analysing the regulation of delta-9 desaturation rate and scd1 expression in human aortic smooth muscle cells (HASMC) exposed to cis and trans C18:1 fatty acid isomers (cis-9 oleic acid, trans-11 vaccenic acid or trans-9 elaidic acid) for 48 h at 100 µM. Treatment of HASMC with these C18:1 fatty acid isomers led to differential effects on delta-9 desaturation; oleic acid repressed the desaturation rate more potently than trans-11 vaccenic acid, whereas trans-9 elaidic acid increased the delta-9 desaturation rate. We then correlated the delta-9 desaturation rate with the expression of scd1 protein and mRNA. We showed that C18:1 fatty acids controlled the expression of scd1 at the transcriptional level in HASMC, leading to an increase in scd1 mRNA content by trans-9 elaidic acid treatment, whereas a decrease in scd1 mRNA content was observed with cis-9 oleic acid and trans-11 vaccenic acid treatments. Altogether, this work highlights a differential capability of C18:1 fatty acid isomers to control scd1 gene expression, which presumes of different consequent effects on cell functions.

Composition of Renaissance paint layers: simultaneous particle induced X-ray emission and backscattering spectrometry.

Particle induced X-ray emission spectroscopy (PIXE) is now routinely used in the field of cultural heritage. Various setups have been developed to investigate the elemental composition of wood/canvas paintings or of cross-section samples. However, it is not possible to obtain information concerning the quantity of organic binder. Backscattering spectrometry (BS) can be a useful complementary method to overcome this limitation. In the case of paint layers, PIXE brings the elemental composition (major elements to traces) and the BS spectrum can give access to the proportion of pigment and binder. With the use of 3 MeV protons for PIXE and BS simultaneously, it was possible to perform quantitative analysis including C and O for which the non-Rutherford cross sections are intense. Furthermore, with the use of the same conditions for PIXE and BS, the experiment time and the potential damage by the ion beam were reduced. The results obtained with the external beam of the Accélérateur Grand Louvre pour l'Analyse Elementaire (AGLAE) facility on various test painting samples and on cross sections from Italian Renaissance masterpieces are shown. Simultaneous combination of PIXE and BS leads to a complete characterization of the paint layers: elemental composition and proportion of the organic binder have been determined and thus provide useful information about ancient oil painting recipes.

Studies of the 6.7 family of dispersed genomic fragments within the MHC class I Region.

Searches for MHC-encoded disease susceptibility genes have led to considerable knowledge of the content of the class I region. In an effort to further understand the nature of the five 6.7 family members previously mapped to this region of the genome, we have further analyzed the cross-reactive members of the family and have observed additional genomic instability within the HLA-A subregion. Such genomic variation may underscore the slower evolutionary rates of the HLA-A allelic family and the extended linkage disequilibrium of markers distal to this locus. Moreover, one of the largest genes associated with a member of the 6.7 family, the 3.8-1 gene found proximal to HLA-B, was found to demonstrate limited, composite similarity to RAG2 and complement C4a gene sequences. A pancreas-specific transcript embedded in a 6.7 cross-reactive fragment was found distal to HLA-H and suggests that the fragments have remained linked to transcriptionally active chromatin comprised of both a major class I gene and a second novel coding sequence since the time of their dispersal. The absence of a 6.7 fragment in the HLA-B subregions of higher nonhuman primates lends credence to the possibility that the great apes have suffered a recent deletion event within this region following the emergence of Homo sapiens.

Systematic sequencing of the human HLA-A/HLA-F region: establishment of a cosmid contig and identification of a new gene cluster within 37 kb of sequence.

The class I region of the human histocompatibility complex is characterized by a high density of genes and pseudogenes and a complex structural organization. To elucidate the complete structure of the HLA-A/HLA-F region with a view to defining its contents in genes and pseudogenes, we developed a strategy of systematic sequencing. This report describes the establishment of a cosmid contig spanning most of the region and the analysis of a 37-kb sequence from one of the cosmids. Four new genes, organized with the HCG-V gene in a clustered structure, have been identified. Two of these contain a zinc finger motif characteristic of DNA-binding proteins. The former, a member of the C3HC4 protein family, is highly expressed in prostate and contains a B30-2-like sequence identified in several genes mapped within the class I region. The latter, which is ubiquitously expressed, is the human equivalent of the yeast polymerase IA12.2 subunit and of the murine tctex6 gene. Of the two other genes, one remains an anonymous gene with no particular feature, while the fourth, specifically expressed in testis, is the human equivalent of the murine tctex4 gene. This cluster, located in a region corresponding to a syntenic unit between mouse and human, appears to be highly conserved.

Structural analysis of the HLA-A/HLA-F subregion: precise localization of two new multigene families closely associated with the HLA class I sequences.

Positional cloning strategies for the hemochromatosis gene have previously concentrated on a target area restricted to a maximum genomic expanse of 400 kb around the HLA-A and HLA-F loci. Recently, the candidate region has been extended to 2-3 Mb on the distal side of the MHC. In this study, 10 coding sequences [hemochromatosis candidate genes (HCG) I to X] were isolated by cDNA selection using YACs covering the HLA-A/HLA-F subregion. Two of these (HCG II and HCG IV) belong to multigene families, as well as other sequences already described in this region, i.e., P5, pMC 6.7, and HLA class 1. Fingerprinting of the four YACs overlapping the region was performed and allowed partial localization of the different multigene family sequences on each YAC without defining their exact positions. Fingerprinting on cosmids isolated from the ICRF chromosome 6-specific cosmid library allowed more precise localization of the redundant sequences in all of the multigene families and revealed their apparent organization in clusters. Further examination of these intertwined sequences demonstrated that this structural organization resulted from a succession of complex phenomena, including duplications and contractions. This study presents a precise description of the structural organization of the HLA-A/HLA-F region and a determination of the sequences involved in the megabase size polymorphism observed among the A3, A24, and A31 haplotypes.

Cloning of a human homologue of the mouse Tctex-5 gene within the MHC class I region.

Using a positional cloning strategy to identify the hemochromatosis gene (HFE), we isolated seven cDNAs by cDNA selection from a region of 400 kilobases (kb) located near the HLA-A and HLA-F loci. In this paper, we report the study of one of the corresponding genes, referred to as HCG V (hemochromatosis candidate gene), localized 150 kb centromeric to HLA-A. This gene was found to be expressed ubiquitously in the form of a 1.8 kb transcript, and to be apparently well conserved during evolution. The gene spanned 3.1 kb and is organized in three exons and two introns. The cDNA of 1620 base pairs (bp) showed an open reading frame of 378 bp, encoding for a 126 amino acid polypeptide which displayed a strong identity with the predicted product of a mouse Tctex-5 gene (t complex, testis expressed) localized in the t complex on chromosome 17. The HCG V gene was assessed as a potential candidate for hemochromatosis in regard to its localization in the linkage disequilibrium area between HFE and polymorphic markers. The study of deletions and point mutations in hemochromatosis patients revealed a single bp polymorphism within the coding region; however, no associated disease changes were found. Therefore we conclude that HCG V is unlikely to be involved in the pathogenesis of hemochromatosis.

A new non-HLA multigene family associated with the PERB11 family within the MHC class I region.

In an effort to initiate steps designed to characterize the idiopathic hemochromatosis disease gene, the HLA-A/HLA-F region where this gene is in disequilibrium linkage with some polymorphic markers has been overlapped by a yeast artificial chromosome (YAC) contig. In order to achieve the physical mapping of these YACs and of the corresponding genomic region, we subcloned one of the YACs involved. A computer-assisted analysis of the sequence of one subclone led to the isolation of a potential exon that proved to belong to a new expressed messenger named HCGIX. After Southern blot analysis, the corresponding cDNA clone was found to belong to a new multigene family whose members are dispersed throughout the HLA class I region and are closely associated with members of another recently described multigene family designated PERB11. The data reported here suggest that these two multigene families form a cluster that have been dispersed together throughout the telomeric part of the major histocompatibility complex and have been involved in the genesis of this human class I region.

Physical map of the HLA-A/HLA-F subregion and identification of two new coding sequences.

As part of an effort to characterize the hemochromatosis gene, we selected three non-chimeric yeast artificial chromosomes (YACs) overlapping with the YAC B30 previously described and forming an 800 kilobase contig covering the HLA-A/HLA-F region. The precise physical map of these YACs and of the corresponding genomic region were established. Nine concentrated sites of CpG cutter elements, potentially HTF islands, were mapped. In addition, several probes have been generated as tools for mapping and examining transcripts produced in the region. This allowed for the characterization and localization of two new coding sequences, provisionally named HCG (for hemochromatosis candidate gene) and numbered VIII and IX.

Speckle-free imaging in four-wave mixing experiments with Bi(12)SiO(20) crystals.

We demonstrate that holographic speckle-free imaging is possible when a dynamic recording medium, such as a Bi(12)SiO(20) crystal, and a four-wave mixing configuration are used. The method is based on time integration in the conjugate-image plane of N coherent images having an independent speckle pattern. We apply this concept to a real-time optical processing operation. A speckle-free time-averaged interferogram of a vibrating structure is obtained.