Recent advances in management of cryptococcal meningitis: commentary

Cryptococcal meningitis remains a substantial health burden with high morbidity, particularly in developing countries. Antifungal treatment regimens are guided by host factors, severity of illness (including presence of complications), and causative cryptococcal species. Recent clinical studies indicate the need for rapidly fungicidal induction therapy regimens using amphotericin B in combination with flucytosine for optimal outcomes. Maintenance therapy with fluconazole is necessary until recovery of immune function. Cryptococcus gattii meningitis requires prolonged induction/eradication therapy. Prompt control of raised intracranial pressure or hydrocephalus is essential. Clinicians should be vigilant for immune restoration-like features. Adjuvant surgery, corticosteroids, and/or recombinant interferon-gamma may be required for large cryptococcomas, cerebral edema, or refractory infection

Whole Genome Sequencing of Australian Candida glabrata Isolates Reveals Genetic Diversity and Novel Sequence Types

Candida glabrata is a pathogen with reduced susceptibility to azoles and echinocandins. Analysis by traditional multilocus sequence typing (MLST) has recognized an increasing number of sequence types (STs), which vary with geography. Little is known about STs of C. glabrata in Australia. Here, we utilized whole genome sequencing (WGS) to study the genetic diversity of 51 Australian C. glabrata isolates and sought associations between STs over two time periods (2002–2004, 2010–2017), and with susceptibility to fluconazole by principal component analysis (PCA). Antifungal susceptibility was determined using Sensititre YeastOneTM Y010 methodology and WGS performed on the NextSeq 500 platform (Illumina) with in silico MLST STs inferred by WGS data. Single nucleotide polymorphisms (SNPs) in genes linked to echinocandin, azole and 5-fluorocytosine resistance were analyzed. Of 51 isolates, WGS identified 18 distinct STs including four novel STs (ST123, ST124, ST126, and ST127). Four STs accounted for 49% of isolates (ST3, 15.7%; ST83, 13.7%; ST7, 9.8%; ST26, 9.8%). Split-tree network analysis resolved isolates to terminal branches; many of these comprised multiple isolates from disparate geographic settings but four branches contained Australian isolates only. ST3 isolates were common in Europe, United States and now Australia, whilst ST8 and ST19, relatively frequent in the United States, were rare/absent amongst our isolates. There was no association between ST distribution (genomic similarity) and the two time periods or with fluconazole susceptibility. WGS identified mutations in the FKS1 (S629P) and FKS2 (S663P) genes in three, and one, echinocandin-resistant isolate(s), respectively. Both mutations confer phenotypic drug resistance. Twenty-five percent (13/51) of isolates were fluconazole-resistant (MIC ≥ 64 μg/ml) of which 9 (18%) had non wild-type MICs to voriconazole and posaconazole. Multiple SNPs were present in genes linked to azole resistance such as CgPDR1 and CgCDR1, as well as several in MSH2; however, SNPs occurred in both azole-susceptible and azole-resistant isolates. Although no particular SNP in these genes was definitively associated with resistance, azole-resistant/non-wild type isolates had a propensity to harbor SNPs resulting in amino acid substitutions in Pdr1 beyond the first 250 amino acid positions. The presence of SNPs may be markers of STs. Our study shows the value of WGS for high-resolution sequence typing of C. glabrata, discovery of novel STs and potential to monitor trends in genetic diversity. WGS assessment for echinocandin resistance augments phenotypic susceptibility testing

Shape selection in non-Euclidean plates

We investigate isometric immersions of disks with constant negative curvature into $\mathbb{R}^3$, and the minimizers for the bending energy, i.e. the $L^2$ norm of the principal curvatures over the class of $W^{2,2}$ isometric immersions. We show the existence of smooth immersions of arbitrarily large geodesic balls in $\mathbb{H}^2$ into $\mathbb{R}^3$. In elucidating the connection between these immersions and the non-existence/singularity results of Hilbert and Amsler, we obtain a lower bound for the $L^\infty$ norm of the principal curvatures for such smooth isometric immersions. We also construct piecewise smooth isometric immersions that have a periodic profile, are globally $W^{2,2}$, and have a lower bending energy than their smooth counterparts. The number of periods in these configurations is set by the condition that the principal curvatures of the surface remain finite and grows approximately exponentially with the radius of the disc. We discuss the implications of our results on recent experiments on the mechanics of non-Euclidean plates

Crystalline Assemblies and Densest Packings of a Family of Truncated Tetrahedra and the Role of Directional Entropic Forces

Polyhedra and their arrangements have intrigued humankind since the ancient Greeks and are today important motifs in condensed matter, with application to many classes of liquids and solids. Yet, little is known about the thermodynamically stable phases of polyhedrally-shaped building blocks, such as faceted nanoparticles and colloids. Although hard particles are known to organize due to entropy alone, and some unusual phases are reported in the literature, the role of entropic forces in connection with polyhedral shape is not well understood. Here, we study thermodynamic self-assembly of a family of truncated tetrahedra and report several atomic crystal isostructures, including diamond, {\beta}-tin, and high- pressure lithium, as the polyhedron shape varies from tetrahedral to octahedral. We compare our findings with the densest packings of the truncated tetrahedron family obtained by numerical compression and report a new space filling polyhedron, which has been overlooked in previous searches. Interestingly, the self-assembled structures differ from the densest packings. We show that the self-assembled crystal structures can be understood as a tendency for polyhedra to maximize face-to-face alignment, which can be generalized as directional entropic forces.Comment: Article + supplementary information. 23 pages, 10 figures, 2 table