Perinuclear Antineutrophil Cytoplasmic Antibody-Associated Ocular Manifestations: Case Series and Literature Review.

PURPOSE: To investigate the diversity of ocular manifestations in patients with positive perinuclear antineutrophil cytoplasmic antibody (p-ANCA). METHODS: The clinical records of five patients exhibiting ocular manifestations and testing positive for serum MPO-ANCA were retrospectively reviewed. RESULTS: Three out of five patients were female. The youngest patient was aged 26, whereas the eldest was 83 years old. 80% (n = 4) of them had purely anterior segment involvement, with the commonest manifestation being peripheral ulcerative keratitis and scleritis. Only one patient had posterior segment involvement, specifically posterior ischemic optic neuropathy. Two patients demonstrated unilateral involvement. There was only one patient diagnosed with systemic involvement, presenting as mixed nephrotic and nephritic syndrome, who required a course of intravenous methylprednisolone during the active stage. Three patients required second-line immunosuppressants throughout the course due to frequent relapse. CONCLUSION: Anterior segment ocular manifestations are not uncommon and can be the initial presentation of p-ANCA-associated vasculitis (AAV). Therefore, its evaluation should be considered in establishing the diagnosis of AAV, a life-threatening disease.

Challenges and Complications of Poly(lactic-co-glycolic acid)-Based Long-Acting Drug Product Development.

Poly(lactic-co-glycolic acid) (PLGA) is one of the preferred polymeric inactive ingredients for long-acting parenteral drug products that are constituted of complex formulations. Despite over 30 years of use, there are still many challenges faced by researchers in formulation-related aspects pertaining to drug loading and release. Until now, PLGA-based complex generic drug products have not been successfully developed. The complexity in developing these generic drug products is not just due to their complex formulation, but also to the manufacturing process of the listed reference drugs that involve PLGA. The composition and product attributes of commercial PLGA formulations vary with the drugs and their intended applications. The lack of standard compendial methods for in vitro release studies hinders generic pharmaceutical companies in their efforts to develop PLGA-based complex generic drug products. In this review, we discuss the challenges faced in developing PLGA-based long-acting injectable/implantable (LAI) drug products; hurdles that are associated with drug loading and release that are dictated by the physicochemical properties of PLGA and product manufacturing processes. Approaches to overcome these challenges and hurdles are highlighted specifically with respect to drug encapsulation and release.

The haplotype-resolved chromosome pairs of a heterozygous diploid African cassava cultivar reveal novel pan-genome and allele-specific transcriptome features.

BACKGROUND: Cassava (Manihot esculenta) is an important clonally propagated food crop in tropical and subtropical regions worldwide. Genetic gain by molecular breeding has been limited, partially because cassava is a highly heterozygous crop with a repetitive and difficult-to-assemble genome. FINDINGS: Here we demonstrate that Pacific Biosciences high-fidelity (HiFi) sequencing reads, in combination with the assembler hifiasm, produced genome assemblies at near complete haplotype resolution with higher continuity and accuracy compared to conventional long sequencing reads. We present 2 chromosome-scale haploid genomes phased with Hi-C technology for the diploid African cassava variety TME204. With consensus accuracy >QV46, contig N50 >18 Mb, BUSCO completeness of 99%, and 35k phased gene loci, it is the most accurate, continuous, complete, and haplotype-resolved cassava genome assembly so far. Ab initio gene prediction with RNA-seq data and Iso-Seq transcripts identified abundant novel gene loci, with enriched functionality related to chromatin organization, meristem development, and cell responses. During tissue development, differentially expressed transcripts of different haplotype origins were enriched for different functionality. In each tissue, 20-30% of transcripts showed allele-specific expression (ASE) differences. ASE bias was often tissue specific and inconsistent across different tissues. Direction-shifting was observed in <2% of the ASE transcripts. Despite high gene synteny, the HiFi genome assembly revealed extensive chromosome rearrangements and abundant intra-genomic and inter-genomic divergent sequences, with large structural variations mostly related to LTR retrotransposons. We use the reference-quality assemblies to build a cassava pan-genome and demonstrate its importance in representing the genetic diversity of cassava for downstream reference-guided omics analysis and breeding. CONCLUSIONS: The phased and annotated chromosome pairs allow a systematic view of the heterozygous diploid genome organization in cassava with improved accuracy, completeness, and haplotype resolution. They will be a valuable resource for cassava breeding and research. Our study may also provide insights into developing cost-effective and efficient strategies for resolving complex genomes with high resolution, accuracy, and continuity.

Mutations in DNA polymerase δ subunit 1 co-segregate with CMD2-type resistance to Cassava Mosaic Geminiviruses.

Cassava mosaic disease (CMD) suppresses cassava yields across the tropics. The dominant CMD2 locus confers resistance to cassava mosaic geminiviruses. It has been reported that CMD2-type landraces lose resistance after regeneration through de novo morphogenesis. As full genome bisulfite sequencing failed to uncover an epigenetic mechanism for this loss of resistance, whole genome sequencing and genetic variant analysis was performed and the CMD2 locus was fine-mapped to a 190 kilobase interval. Collectively, these data indicate that CMD2-type resistance is caused by a nonsynonymous, single nucleotide polymorphism in DNA polymerase δ subunit 1 (MePOLD1) located within this region. Virus-induced gene silencing of MePOLD1 in a CMD-susceptible cassava variety produced a recovery phenotype typical of CMD2-type resistance. Analysis of other CMD2-type cassava varieties identified additional candidate resistance alleles within MePOLD1. Genetic variation of MePOLD1, therefore, could represent an important genetic resource for resistance breeding and/or genome editing, and elucidating mechanisms of resistance to geminiviruses.

A case series with literature review on adjunctive usage of intravitreal ceftazidime in ocular syphilis with human immunodeficiency virus infection.

BACKGROUND: Penicillin is the conventional treatment for all stages of syphilis, including ocular and neurosyphilis, according to the recommendations by the Centre for Disease Control and Prevention Sexually Transmitted Disease. This case series highlighted three cases of ocular syphilis which showed prompt treatment response as early as 24 h after the adjunctive intravitreal ceftazidime injection. METHODS: Case Series. RESULTS: In case 1, there was significant improvement in the vision and vitritis after 24 h of a single intravitreal ceftazidime injection. In case 2, the patient achieved his best vision after a total of three intravitreal injections in his left eye and one in his right eye. In case 3, there was a further resolution of perivascular sheathing and retinal haemorrhages seen 1 week after a single intravitreal ceftazidime injection. CONCLUSION: The efficacy of intravitreal ceftazidime injection as a local adjunctive therapy in ocular syphilis treatment is noteworthy. It can be considered in cases which show suboptimal or slower treatment response despite early commencement of systemic penicillin to prevent devastating ocular sequelae.