Evolution and transmission of antibiotic resistance is driven by Beijing lineage Mycobacterium tuberculosis in Vietnam

A previous investigation has elucidated the landscape of Mtb genomic diversity and transmission dynamics in Ho Chi Minh City, Vietnam. Here, we expand the scope of this survey by adding a substantial number of additional genomes (total sample size: 2,542) and phenotypic drug susceptibility data for the majority of isolates. We aim to explore the prevalence and evolutionary dynamics of drug resistance and our ability to predict drug resistance from sequencing data. Among isolates tested phenotypically against first-line drugs, we observed high rates of streptomycin [STR, 37.7% ( N = 573/1,520)] and isoniazid resistance [INH, 25.7% ( N = 459/1,786)] and lower rates of resistance to rifampicin [RIF, 4.9% ( N = 87/1,786)] and ethambutol [EMB, 4.2% ( N = 75/1,785)]. Relative to global benchmarks, resistance to STR and INH was predicted accurately when applying the TB-Profiler algorithm to whole genome sequencing data (sensitivities of 0.81 and 0.87, respectively), while resistance to RIF and EMB was predicted relatively poorly (sensitivities of 0.70 and 0.44, respectively). Exploring the evolution of drug resistance revealed the main phylogenetic lineages to display differing dynamics and tendencies to evolve resistance via mutations in certain genes. The Beijing sublineage L2.2.1 was found to acquire de novo resistance mutations more frequently than isolates from other lineages and to suffer no apparent fitness cost acting to impede the transmission of resistance. Mutations conferring resistance to INH and STR arose earlier, on average, than those conferring resistance to RIF and are now more widespread across the phylogeny. The high prevalence of “background” INH resistance, combined with high rates of RIF mono-resistance (20.7%, N = 18/87), suggests that rapid assays for INH resistance will be valuable in this setting. These tests will allow the detection of INH mono-resistance and will allow multi-drug-resistant isolates to be distinguished from isolates with RIF mono-resistance. IMPORTANCE Drug-resistant tuberculosis (TB) infection is a growing and potent concern, and combating it will be necessary to achieve the WHO’s goal of a 95% reduction in TB deaths by 2035. While prior studies have explored the evolution and spread of drug resistance, we still lack a clear understanding of the fitness costs (if any) imposed by resistance-conferring mutations and the role that Mtb genetic lineage plays in determining the likelihood of resistance evolution. This study offers insight into these questions by assessing the dynamics of resistance evolution in a high-burden Southeast Asian setting with a diverse lineage composition. It demonstrates that there are clear lineage-specific differences in the dynamics of resistance acquisition and transmission and shows that different lineages evolve resistance via characteristic mutational pathways

HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): a randomised controlled trial of hyperbaric oxygen to prevent osteoradionecrosis of the irradiated mandible: study protocol for a randomised controlled trial

Background: Osteoradionecrosis of the mandible is the most common serious complication of radiotherapy for head and neck malignancy. For decades, hyperbaric oxygen has been employed in efforts to prevent those cases of osteoradionecrosis that are precipitated by dental extractions or implant placement. The evidence for using hyperbaric oxygen remains poor and current clinical practice varies greatly. We describe a protocol for a clinical trial to assess the benefit of hyperbaric oxygen in the prevention of osteoradionecrosis during surgery on the irradiated mandible. Methods/design: The HOPON trial is a phase III, randomised controlled, multi-centre trial. It employs an unblinded trial design, but the assessment of the primary endpoint, i.e. the diagnosis of osteoradionecrosis, is assessed on anonymised clinical photographs and radiographs by a blinded expert panel. Eligibility is through the need for a high-risk dental procedure in the mandible where at least 50-Gy radiotherapy has been received. Patients are randomised 1:1 to hyperbaric oxygen arm (Marx protocol) : control arm, but both groups receive antibiotics and chlorhexidine mouthwash. The primary endpoint is the presence of osteoradionecrosis at 6 months following surgery, but secondary endpoints include other time points, acute symptoms and pain, quality of life, and where implants are placed, their successful retention. Discussion: The protocol presented has evolved through feasibility stages and through analysis of interim data. The classification of osteoradionecrosis has undergone technical refinement to ensure that robust definitions are employed. The HOPON trial is the only multi-centre RCT conducted in this clinical setting despite decades of use of hyperbaric oxygen for the prevention of osteoradionecrosis. Trial registration: European Clinical Trials Database, ID: EudraCT200700622527. First registered on 5 November 2007

Equitable expanded carrier screening needs Indigenous clinical and population genomic data

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government’s Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government’s objectives and its commitment “to leveraging the benefits of genomics in the health system for all Australians.” They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged