Research progress on biodegradable polymeric platforms for targeting antibiotics to the bone.

The treatment of bone infections still involves systemic or local antibiotic therapy in high doses for prolonged periods. Current research focuses on the application of different drug delivery systems to the bone, aiming at a targeted local administration that will decrease the number of drugs used and their toxicity, compared to the systemic route. The gold standard in clinical practice is currently poly(methyl methacrylate) (PMMA) cement. The main drawback of PMMA, however, is that it is non-biodegradable, requiring a second follow-up surgery to remove the implant. Biodegradable delivery systems, on the other hand, are easily resorbable within the organism, and less invasive alternative with better patient compliance. Among biodegradable materials, natural and synthetic polymers are being studied as local drug delivery systems due to their excellent biocompatibility, sustained effect, and antibiotic release with high penetrability to infected bone and soft tissue. In this review, we focus on biodegradable polymeric platforms, such as micro- and nanoparticles, scaffolds, and hydrogels, as well as multi-delivery systems for targeting antibiotics to the bone. Additionally, we discuss the reported drug release profiles that provide important information about the systems' functionality.

Poly(DL-lactic acid) scaffolds as a bone targeting platform for the co-delivery of antimicrobial agents against S. aureus-C.albicans mixed biofilms.

New strategies for the treatment of polymicrobial bone infections are required. In this study, the co-delivery of two antimicrobials by poly(D,L-lactic acid) (PDLLA) scaffolds was investigated in a polymicrobial biofilm model. PDLLA scaffolds were prepared by solvent casting/particulate leaching methodology, incorporating minocycline and voriconazole as clinically relevant antimicrobial agents. The scaffolds presented a sponge-like appearance, suitable to support cell proliferation and drug release. Single- and dual-species biofilm models of Staphylococcus aureus and Candida albicans were developed and characterized. S. aureus presented a higher ability to form single-species biofilms, compared to C. albicans. Minocycline and voriconazole-loaded PDLLA scaffolds showed activity against S. aureus and C. albicans single- and dual-biofilms. Ultimately, the cytocompatibility/functional activity of PDLLA scaffolds observed in human MG-63 osteosarcoma cells unveil their potential as a next-generation co-delivery system for antimicrobial therapy in bone infections.

The effects of waste sorting in environmental microbiome, THP-1 cell viability and inflammatory responses.

Workers in the waste sorting industry are exposed to diverse bioaerosols. Characterization of these bioaerosols is necessary to more accurately assess the health risks of exposure. The use of high-throughput DNA sequencing for improved analysis of microbial composition of bioaerosols, in combination with their in vitro study in relevant cell cultures, represents an important opportunity to find answers on the biological effects of bioaerosols. This study aimed to characterize by high-throughput sequencing the biodiversity present in complex aerosol mixtures retained in forklift air conditioning filters of a waste-sorting industry and its effects on cytotoxicity and secretion of proinflammatory cytokines in vitro using human macrophages derived from monocytic THP-1 cells. Seventeen filters from the filtration system from forklifts operating in one waste sorting facility and one control filter (similar filter without prior use) were analyzed using high-throughput sequencing and toxicological tests in vitro. A trend of positive correlation was seen between the number of bacterial and fungal OTUs (r = 0.47, p = 0.06). Seven filters (39%) exhibited low or moderate cytotoxicity (p < 0.05). The highest cytotoxic responses had a reduction in cell viability between 17 and 22%. Filter samples evoked proinflammatory responses, especially the production of TNFα. No significant correlation was found between fungal richness and inflammatory responses in vitro. The data obtained stress the need of thorough exposure assessment in waste-sorting industry and to take immunomodulatory properties into consideration for bioaerosols hazard characterization. The broad spectrum of microbial contamination detected in this study demonstrates that adequate monitoring of bioaerosol exposure is necessary to evaluate and minimize risks. The combined techniques can support the implementation of effective environmental monitoring programs of public and occupational health importance.

PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease.

Maturity-Onset Diabetes of the Young (MODY) type 4 or PDX1 -MODY is a rare form of monogenic diabetes caused by heterozygous variants in PDX1 . Pancreatic developmental anomalies related to PDX1 are reported only in neonatal diabetes cases. Here, we describe dorsal pancreatic agenesis in 2 patients with PDX1 -MODY. The proband presented with diabetes since 14 years of age and maintained regular glycemic control with low doses of basal insulin and detectable C-peptide levels after 38 years with diabetes. A diagnosis of MODY was suspected. Targeted next-generation sequencing identified a heterozygous variant in PDX1 : c.188delC/p.Pro63Argfs*60. Computed tomography revealed caudal pancreatic agenesis. Low fecal elastase indicated exocrine insufficiency. His son had impaired glucose tolerance, presented similar pancreatic agenesis, and harbored the same allelic variant. The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1 -related diabetes diagnosed after the first year of life. This finding can improve the management of MODY4 patients, leading to precocious investigation of pancreatic dysgenesis and exocrine dysfunction.

Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families.

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.