Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala

BACKGROUND: Improved point-of-care diagnostic tests for tuberculosis (TB) in severe immune suppressed people living with HIV (PLWH) are needed to decrease morbidity and mortality outcomes. The aim of the study is to evaluate the performance of the lipoarabinomannan antigen test (LAM-test) with and without α-mannosidase pre-treated urine in a cohort of PLWH in primary care clinics in Guatemala. We further determined TB incidence, and mortality rates and its risk factors in PLWH with TB symptoms. METHODS: Prospective longitudinal study of PLWH with TB symptoms. Urine samples were collected at 2 HIV sites to test the sensitivity of the LAM-test in urine with and without α-mannosidase pre-treatment. A composite reference standard of either a positive Mycobacterium tuberculosis complex culture and/or GeneXpert RESULTS: The overall sensitivity of the LAM-test was of 56.1% with 95% CI of (43.3-68.3). There were no differences in the LAM-test sensitivity neither by hospital nor by CD4 T cell values. LAM-test sensitivity in PLWH with \u3c 200 CD4 T cells/µl was of 62.2% (95% CI 46.5-76.2). There were no significant differences in sensitivity when comparing LAM-test results obtained from untreated vs. α-mannosidase treated urine [55.2% (95% CI 42.6-67.4) vs. 56.9% (95% CI 44-69.2), respectively]. TB incidence in our cohort was of 21.4/100 person years (PYs) (95% CI 16.6-27.6), and mortality rate was of 11.1/100 PYs (95% CI 8.2-15.0). Importantly, PLWH with a positive LAM-test result had an adjusted hazard ratio (aHR) of death of 1.98 (1.0-3.8) with a significant p value of 0.044 when compared to PLWH with a negative LAM-test result. CONCLUSIONS: In this study, α-mannosidase treatment of urine did not significantly increase the LAM-test performance, however; this needs to be further evaluated in a large-scale study due to our study limitations. Importantly, high rates of TB incidence and mortality were found, and a positive LAM-test result predicted mortality in PLWH with TB clinical symptoms

Germline loss-of-function variants in the base-excision repair gene MBD4 cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and -uniquely amongst CRC predisposition syndromes- to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the genetic diagnosis of polyposis and/or early-onset AM

3D printed nanofiltration composite membranes with reduced concentration polarisation

3D printed nanofiltration (NF) composite membranes with surface patterns minimising the impact of concentration polarisation (CP) are presented here for the first time. The membranes consist of a NF polydopamine‐coated polyvinylidene fluoride (PVDF/PDA) selective layer on a 3D printed asymmetric wavy (patterned) support. The result is a wavy composite membrane with pure water permeance of 14 ± 2 LMH bar−1 and molecular weight cut-off of ∼550 Da, measured using a crossflow NF setup at a transmembrane pressure of 2 bar for Reynold number (Re) of 700, using a range of dyes (mass balance &gt;97% for all tests). The CP behaviour of the composite membranes was assessed by filtration of Congo red (CR) dye solution (0.01 g L−1), showing that the wavy pattern significantly reduced the impact of CP compared to the flat membranes, with a nearly tripling of the mass transfer coefficient and a 57% decline of the CP factor. Computational fluid dynamics showed that these significant performance improvements were due to improved hydrodynamics, with the maximum surface shear stress induced by the wavy structure (1.35 Pa) an order of magnitude higher than that of the flat membranes (0.18 Pa) at Re = 700. These results demonstrate that 3D printing is a viable technology route to reducing concentration polarisation in membrane nanofiltration applications.</p

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management. Keywords: 5′-methylcytosine deamination; colorectal cancer; mutational signature; mutator phenotype; polyposi

3D printed porous contactors for enhanced oil droplet coalescence

The fabrication of 3D printed porous contactors based on triply periodic minimal surfaces (TPMS) is reported here for the first time. The structures, based on the Schwarz-P and Gyroid TPMS, were tested for oil-in-water demulsification via oil droplet coalescence and compared to a contactor with cylindrical pores and natural separation. The contactors were characterized in terms of intrinsic permeability, resistance and oil separation efficiency, for different oil concentrations (0.3, 0.4, 0.5 vol%) in the oil-in-water emulsion, vacuum pressures (10 and 20 mbar) and thickness of the contactors (4.68 and 9.36 mm). Results show that while the Gyroid contactor has the highest resistance and lowest intrinsic permeability of all three structures, it has 18% and 5% higher separation efficiency than the cylindrical and Schwarz-P structures, respectively. These characteristics reflect the higher tortuosity and surface area of the Gyroid structure compared to the other two. At 90%, the Gyroid structure also has a 22% higher separation efficiency and a two order of magnitude higher separation rate for the permeate compared to natural coalescence, attributed to an 8-fold increase in oil droplet diameter of the permeate compared to the feed, as a result of passage through the contactor. Higher vacuum pressure and higher contactor thickness further increase the separation efficiency of all structures, but the effect is more pronounced for the Gyroid structure due to its higher tortuosity. These results show that 3D printing is an effective tool for the design of porous contactors where a high surface area of interaction is key to their success, paving their way to extended use in a variety of industrial applications.</p

3D printed composite membranes with enhanced anti-fouling behaviour

The fabrication of three dimensional (3D) printed composite membranes by depositing a thin polyethersulfone (PES) selective layer onto ABS-like 3D printed flat and wavy structured supports is presented here for the first time. The 50 mm disk supports were printed using an industrial 3D printer with both flat and double sinusoidal, i.e. wavy, surface structures. The thin selective layers were deposited onto the 3D supports via vacuum filtration. The resulting flat and wavy composite membranes were characterised and tested in terms of permeance, rejection, and cleanability by filtering oil-in-water emulsions of 0.3−0.5 vol% through a cross-flow (Reynolds number, Re = 100, 500 and 1000) ultrafiltration set-up under a constant transmembrane pressure of 1 bar. Results showed that pure water permeance through the wavy membrane was 30% higher than the flat membrane for Re = 1000. The wavy 3D printed membrane had a 52% higher permeance recovery ratio compared to the flat one after the first filtration cycle, with both membranes having an oil rejection of 96% ± 3%. The wavy 3D composite membrane maintained some level of permeation after 5 complete filtration cycles using only water as the cleaning/rinsing agent, whereas the flat one was completely fouled after the first cycle. Cleaning with NaOCl after the sixth cycle restored ~70% of the initial permeance for the wavy membrane. These results demonstrate that 3D printed wavy composite membranes can be used to significantly improve permeation and cleanability performance, particularly in terms of reducing fouling build-up, i.e. the main obstacle limiting more widespread adoption of membranes in industrial applications.</p

Comparative genomic analysis of a multidrug-resistant Staphylococcus hominis ShoR14 clinical isolate from Terengganu, Malaysia, led to the discover of novel mobile genetic elements

Staphylococcus hominis is a coagulase-negative Staphylococcus (CoNS) commensal capable of causing serious systemic infections in humans. The emergence of multidrug-resistant S. hominis strains is of concern but little is known about the characteristics of this organism, particularly from Malaysia. Here, we present the comparative genome analysis of S. hominis ShoR14, a multidrugresistant, methicillin-resistant blood isolate from Terengganu, Malaysia. Genomic DNA of S. hominis ShoR14 was sequenced on the Illumina platform and assembled using Unicycler v0.4.8. ShoR14 belonged to sequence type (ST) 1 which is the most prevalent ST of the S. hominis subsp. hominis. Comparative genomic analysis with closely related strains in the database with complete genome sequences, led to the discovery of a novel variant of the staphylococcal chromosome cassette mec (SCCmec) type VIII element harboring the mecA methicillin-resistance gene in ShoR14 and its possible carriage of a SCCfus element that encodes the fusidic acid resistance gene (fusC). Up to seven possible ShoR14 plasmid contigs were identified, three of which harbored resistance genes for tetracycline (tetK), chloramphenicol (catA7), macrolides, lincosamides, and streptogramin B (ermC). Additionally, we report the discovery of a novel mercury-resistant transposon, Tn7456, other genomic islands, and prophages which make up the S. hominis mobilome