Genetic variation in tuberculosis is influenced by the host environment, patients with comorbidity, and tuberculosis–type 2 diabetes mellitus (TB-T2DM) and implies a higher risk of treatment failure and development of drug resistance. Considering the above, this study aimed to evaluate the influence of T2DM on the dynamic of polymorphisms related to antibiotic resistance in TB. Fifty individuals with TB-T2DM and TB were initially characterized, and serial isolates of 29 of these individuals were recovered on day 0 (diagnosis), 30, and 60. Genomes were sequenced, variants related to phylogeny and drug resistance analyzed, and mutation rates calculated and compared between groups. Lineage X was predominant. At day 0 (collection), almost all isolates from the TB group were sensitive, apart from four isolates from the TB-T2DM group showing the mutation katG S315T, from which one isolate had the mutations rpoB S450L, gyrA A90G, and gyrA D94G. This pattern was observed in a second isolate at day 30. The results provide a first overview of the dynamics of mutations in resistance genes from individuals with TB-T2DM, describing an early development of resistance to isoniazid and a rapid evolution of resistance to other drugs. Although preliminary, these results help to explain the increased risk of drug resistance in individuals with TB and T2DM.

Genes related to DNA damage repair in Mycobacterium tuberculosis are critical for survival and genomic diversification. The aim of this study is to compare the presence of SNPs in genes related to DNA damage repair in sensitive and drug-resistant M. tuberculosis genomes isolated from patients with and without type 2 diabetes mellitus (T2DM). We collected 399 M. tuberculosis L4 genomes from several public repositories; 224 genomes belonging to hosts without T2DM, of which 123 (54.9%) had drug sensitive tuberculosis (TB) and 101 (45.1%) had drug resistance (DR)-TB; and 175 genomes from individuals with T2DM, of which 100 (57.1%) had drug sensitive TB and 75 (42.9%) had DR-TB. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed and compared with the resistance profile and the presence/absence of T2DM in the host. The results show the phylogenetic relationships of some SNPS and L4 sub-lineages, as well as differences in the distribution of SNPs present in DNA damage repair-related genes related to the resistance profile of the infecting strain and the presence of T2DM in the host. Given these differences, it was possible to generate two discriminant functions to distinguish between drug sensitive and drug resistant genomes, as well as patients with or without T2DM.

Efflux pumps are proteins related to the transport of molecules in bacteria, and some of them have been recently reported to be involved in drug resistance (DR) in Mycobacterium tuberculosis. In addition, the association with type 2 diabetes mellitus (T2DM) has been considered a factor favoring the development of drug resistance. Therefore, the aim of this study was to characterize, by analysis of M. tuberculosis genomes, the variants in efflux pump genes and to determine the level of association with T2DM and DR. Nearly 400 Mtb genomes from individuals with and without T2DM and with and without DR were recovered. Of the 164 efflux pump genes analyzed, 10 lack any variant, while 154 genes presented from 3 to 19 variants. The variant S217P in mmpL13a (Rv1145) was the most abundant, found in 98 (25%) isolates. A significant association was observed between 19 variants and DR, and between 20 variants and T2DM (p ≤ 0.005). Although preliminary, the results show a tendency for certain variants to appear in tuberculosis isolates from individuals with DR and T2DM, demonstrating the possible influence of the host in the evolution of tuberculosis. Further studies are necessary to confirm the participation of these variants in the efflux pump function in tuberculosis.

Coordination of care can be improved through an intervention or a combination of several ones. In addition, it is recommended to encourage the active involvement of professionals in the design, implementation and assessment of coordination mechanisms. To analyse the factors that influence the implementation of participatively designed interventions and their effects on clinical coordination between levels of care in a public healthcare network of health services in Xalapa, Veracruz, Mexico. A qualitative, descriptive-interpretative study, for which individual interviews and discussion groups with a criterion sample of participants: Local Steering Committee and the Professional Platform. A content analysis, with mixed category generation and segmentation by intervention and topics, was carried out. According to the problem analysis, participants designed two sequential interventions: offline virtual consultation, and joint training meetings on maternal health and chronic diseases. Respondents perceived a differentiated impact on clinical coordination according to intervention: greater in the case of joint maternal health trainings and limited for the chronic diseases meetings, as they were the offline virtual consultation was rarely used. The involvement of professionals in designing the interventions, as well as institutional support and reflexive methods for training, all decisively improved clinical coordination between levels.

Resumen: El objetivo fue analizar el nivel y caracterizar el uso de mecanismos de coordinación clínica entre niveles de atención, y sus factores asociados, en dos redes públicas de servicios de salud en México. Se realizó estudio transversal mediante el cuestionario COORDENA a médicos de atención primaria y especializada del estado de Veracruz. Se encontraron diferencias entre redes y niveles de atención, según el mecanismo. En ambas, la referencia/contrarreferencia es sobre todo utilizada para canalizar al paciente a otro nivel, principalmente por parte de los médicos de atención primaria. Se identificó una alta recepción de referencias por especialistas, pero escasa recepción de contrarreferencias en atención primaria. Ser hombre y reconocer al médico/a de atención primaria como responsable del seguimiento del paciente en su trayectoria asistencial, fueron factores asociados al envío frecuente de la contrarreferencia por especialistas. El informe de alta se utiliza en ambas redes para enviar información clínica al otro nivel, con mayor envío por médicos/as especialistas, y con menor recepción en atención primaria. En ambas redes, el seguimiento a las recomendaciones de los mecanismos para estandarizar la atención clínica (guías de práctica clínica, etc.) por parte médicos/as de atención primaria que de especializada. La utilización de mecanismos de coordinación entre niveles de atención es deficiente y limitada, con mayor uso de mecanismos para transferir información que para la gestión clínica. Se evidencia la necesidad de implementar estrategias que consideren la participación de los profesionales, para favorecer la adaptación local, apropiación y mejorar su uso.

The presence of SNPs in genes related to DNA damage repair in M. tuberculosis can trigger hypermutagenic phenotypes with a higher probability of generating drug resistance. The aim of this research was to compare the presence of SNPs in genes related to DNA damage repair between sensitive and DR isolates, as well as to describe the dynamics in the presence of SNPs in M. tuberculosis isolated from recently diagnosed TB patients of the state of Veracruz, Mexico. The presence of SNPs in the coding regions of 65 genes related to DNA damage repair was analyzed. Eighty-six isolates from 67 patients from central Veracruz state, Mexico, were sequenced. The results showed several SNPs in 14 genes that were only present in drug-resistant genomes. In addition, by following of 15 patients, it was possible to describe three different dynamics of appearance and evolution of non-synonymous SNPs in genes related to DNA damage repair: 1) constant fixed SNPs, 2) population substitution, and 3) gain of fixed SNPs. Further research is required to discern the biological significance of each of these pathways and their utility as markers of DR or for treatment prognosis.