Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer ...protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L SD 2·9) to week 26 (4·3 mmol/L 2·5; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
Knowledge of the microbiological quality and prevalence of antibiotic resistance and virulence genes in bacterial isolates from leafy green vegetables supplied by formal suppliers (retailers) and ...informal suppliers (street vendors) in South Africa is limited. Because leafy vegetables have been implicated in foodborne disease outbreaks worldwide, 180 cabbage and spinach samples were collected from three major retailers and nine street vendors in Johannesburg, South Africa. Escherichia coli and coliforms were enumerated using Petrifilm plates. The prevalence of Listeria monocytogenes, Salmonella, and Shigella was determined using real-time PCR analysis. Identities of presumptive E. coli isolates from the fresh produce were confirmed using matrix-assisted laser desorption-ionization time of flight mass spectroscopy. Isolates were characterized using phenotypic (antibiotic resistance) and genotypic (phylogenetic and virulence gene) analysis. Hygiene indicator bacteria levels on spinach from formal and informal retailers exceeded the maximum level specified by the Department of Health guidelines for fresh fruit and vegetables. E. coli counts for street vendor spinach were higher (P < 0.0789) than those for retailer spinach. E. coli was present in only two cabbage samples, at 0.0035 CFU/g. L. monocytogenes and Salmonella were detected in 7.2 and 5% of the 180 samples, respectively, based on real-time PCR analysis; Shigella was not detected. Of the 29 spinach E. coli isolates, 37.9% were multidrug resistant. Virulence genes eae and stx
were present in 14 and 3% of the spinach E. coli isolates, respectively; the stx
gene was not detected. Eighty-six percent of these isolates belonged to phylogroup A, 3% belonged to group C, 7% belonged to group E, and 3% belonged to clade 1. The results from the current exploratory study on the microbiological quality of spinach bought from selected retailers highlight the need for continued surveillance on a larger scale, especially in the informal sector, to characterize the potential health risks to the consumer.
To evaluate the microbiological safety, potential multidrug-resistant bacterial presence and genetic relatedness (DNA fingerprints) of Escherichia coli isolated from the water-soil-plant nexus on ...highly diverse fresh produce smallholder farms.
Irrigation water (n = 44), soil (n = 85), and fresh produce (n = 95) samples from six smallholder farms with different production systems were analysed for hygiene indicator bacterial counts and the presence of shigatoxigenic E. coli and Salmonella spp. using standard microbiological methods. Identities of isolates were confirmed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), and the genetic relatedness of the E. coli isolates determined using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) analysis. Irrigation water E. coli levels ranged between 0 and 3.45 log MPN/100 ml-1 with five farms having acceptable levels according to the World Health Organization limit (3 log MPN/100 ml-1). Fresh produce samples on four farms (n = 65) harboured E. coli at low levels (<1 log CFU/g-1) except for one sample from kale, spring onion, green pepper, onion, and two tomato samples, which exceeded international acceptable limits (100 CFU/g-1). Only one baby carrot fresh produce sample tested positive for Salmonella spp. Of the 224 samples, E. coli isolates were identified in 40% (n = 90) of all water, soil, and fresh produce types after enrichment. Additionally, the DNA fingerprints of E. coli isolates from the water-soil-plant nexus of each respective farm clustered together at high similarity values (>90%), with all phenotypically characterized as multidrug-resistant.
The clustering of E. coli isolated throughout the water-soil-plant nexus, implicated irrigation water in fresh produce contamination. Highlighting the importance of complying with irrigation water microbiological quality guidelines to limit the spread of potential foodborne pathogens throughout the fresh produce supply chain.
Abstract
The application of permanent areal support is recognised as a measure to either retain or prevent the mobilization of potentially unstable keyblocks between installed support elements. ...Various areal support methods have been developed to provide support to the freshly exposed area created by the blast and to provide support between existing support elements. These methods consist of either shotcrete, thin spray-on liners (TSL), blast resistant mesh or temporary (removable) nets. This paper focuses on the application of polymer-modified cementitious TSLs which is the type predominantly applied in South-African underground mines. Significant amounts of research has been conducted on TSLs. The majority of the research consisted of predominantly laboratory testing. The results of the tests only provide an output which can be used to measure a specific characteristic (i.e. tensile strength) against other products. The output obtained from laboratory tests are not understood, cannot be benchmarked against good or poor performing products or quantitatively related to the performance of the product when applied
in-situ
on a large scale. This situation is problematic as different support suppliers make claims in terms of the performance of their products based on a material property or small scale testing. The behavioural mechanism of a rockmass supported by TSLs is not understood. It is therefore not clear what critical TSL parameters will affect rockmass stability. Very little work has been conducted locally to test the
in-situ
behaviour of TSLs once applied. An extensive testing program was developed to establish how the material properties of a TSL as tested in a laboratory would relate to small and large scale
in-situ
behaviour. This paper discusses the testing conducted and the high level findings.
•Multidrug-resistant and multivirulent Salmonella spp. are present within the small-scale leafy green vegetable production and supply chains.•Multidrug-resistant Salmonella spp. presence (92.4%) in ...the water-plant-food nexus.•All isolated Salmonella spp. possessed the aac(6')-Iaa antimicrobial resistance gene.•All isolated Salmonella spp. harbored Salmonella Pathogenicity Islands 1, 2, and 3.•Salmonella Typhimurium and Salmonella Enteritidis possessed plasmid replicons IncFIB(S) and IncFII(S).
Salmonella have been implicated in foodborne disease outbreaks globally and is a pressing concern in the South African small-scale sector due to inadequate hygiene standards and limited regulatory oversight, leading to a higher risk of foodborne diseases. By investigating irrigation water and leafy green vegetables produced by small-scale growers and sold through unregulated supply chains, this study was able to determine the presence, serotype distribution, virulence gene profiles, antibiotic resistance, and genetic diversity of Salmonella isolated from these sources. From 426 samples, 21 Salmonella-positive samples were identified, providing 53 Salmonella isolates. Of these, six different Salmonella serotypes and sequence types (STs) were identified, including Salmonella II 42:r: ST1208 (33.96%; n = 18), Salmonella Enteritidis: ST11 (22.64%; n = 12), Salmonella II 42:z29: ST4395 (16.98%; n = 9), Salmonella Havana: ST1524 (15.09%; n = 8), Salmonella Typhimurium: ST19 (9.43%; n = 5), and Salmonella IIIb 47:i:z: ST7890 (1.89%; n = 1). A total of 92.45% of the isolates were found to be multidrug-resistant, showing high rates of resistance to aztreonam (88.68%; n = 47), ceftazidime (86.79%; n = 46), nalidixic acid (77.36%; n = 41), cefotaxime (75.47%; n = 40), cefepime (71.70%; n = 38), and streptomycin (69.81%; n = 37). All isolates possessed the aac(6')-Iaa antimicrobial resistance gene, with a range of between 9 and 256 virulence genes. Eleven cluster patterns were observed from Enterobacterial Repetitive Intergenic Consensus sequence analyses, demonstrating high diversity among the Salmonella spp., with water and fresh produce isolates clustering, suggesting water as a potential contamination source. Plasmid replicon types were identified in 41.51% (n = 22) of the isolates, including Col(pHAD28) in Salmonella Havana (5.66%; n = 3), Col156 in Salmonella II 42:z29:- (1.89%; n = 1) and both IncFIB(S) and IncFII(S) in Salmonella Enteritidis (22.64; n = 12), Salmonella Typhimurium (9.43%; n = 5), and Salmonella Havana (1.89%; n = 1). This study highlights the presence of multidrug-resistant and multivirulent Salmonella spp. in the small-scale leafy green vegetable supply chains, underscoring the need for the development of a “fit-for-purpose” food safety management system within this system.
This paper investigates the use of a thin spray-on liner (TSL) as stope face support in narrow width tabular stopes. The application of areal support is difficult in these stopes because of the small ...stoping width and the large area of hanging wall that is exposed by the long face lengths and regular blasting. A simple analytical model of a collapsing block supported by a TSL is explored to determine the parameters to be considered for underground use of the liners. Most literature on TSL focusses mostly on specialised laboratory testing. Almost no large scale testing to determine TSL strengths, when it is applied to blocky rock masses, has been conducted. To simulate the discontinuous nature of the hanging wall in mining stopes, a large scale rig and test methodology was developed. Four different polymer-modified cementitious TSL products were tested and the results are described in the paper. For the particular experimental setup and a curing time of 24 h, the maximum load carrying capacity of the strongest TSL was 305 kg, while a 50 mm thick shotcrete had a capacity exceeding 1100 kg. The test results indicate that care should be exercised when attempting to use a TSL as a structural element in support systems.
As a historic gold mining area, the City of Benoni has numerous water bodies close to major tailings dams and mine dumps. Here we assess spatial patterns in the sediment geochemistry of five dams and ...four natural pans within a 5-km radius of the core mining area to determine the degree of contamination7 by mining-associated pollutants. XRF analysis was used with a geoaccumulation index to assess the degree of contamination above background levels. Prevailing winds blow from the north and north-west with less dominant winds from the east. Sediment concentrations of As, Cu, Pb, Ni and Zn are highly correlated across the region, suggestive of a common source. Except for one pan showing evidence of local industrial pollution, the most contaminated sites are the dams to the west of the mine dumps where concentrations of As, Cu, Pb and Zn increase towards the central mining area, with highest trace metal concentrations in Kleinfontein Dam, adjacent to a reworked mine dump. Sites upwind of the central mining area showed little evidence of mining-related contamination. Trace contaminant concentrations in sediments of these dams are much greater than those found in the nearby Springs-Blesbokspruit wetlands adjacent to more recently active mines. The potential risks to aquatic ecosystems and recreational users of these urban and suburban water bodies from these wind-blown, legacy mining contaminants merit further investigation.
West Nile virus (WNV), a mosquito-borne flavivirus, is endemic to South Africa. However, its contribution to acute febrile and neurological disease in hospitalized patients in South Africa is ...unknown. This study examined two patient cohorts for WNV using molecular testing and IgM serology with confirmation of serological results by viral neutralization tests (VNT) to address this knowledge gap. Univariate analysis was performed using collected demographic and clinical information to identify risk factors. In the first cohort, 219 cerebrospinal fluid (CSF) specimens from patients with acute neurological disease in Gauteng hospitals collected in January to June 2017 were tested for WNV. The study identified WNV in 8/219 (3.65%, 95.00% CI (1.59-7.07)) patients with unsolved neurological infections. The second cohort, from 2019 to 2021, included 441 patients enrolled between January and June with acute febrile or neurological disease from urban and rural sites in Gauteng and Mpumalanga provinces. West Nile virus was diagnosed in 40/441 (9.07%, 95.00% CI (6.73-12.12)) of patients, of which 29/40 (72.50%, 95.00% CI (56.11-85.40)) had neurological signs, including headaches, encephalitis, meningitis, and acute flaccid paralysis (AFP). Notably, most of the cases were identified in children although adolescents and senior adults had a significantly higher risk of testing WNV positive. This suggests a previously underestimated disease burden and that WNV might be underrecognized as a cause of febrile and neurological diseases in hospitalized patients in South Africa, especially in children. This emphasizes the importance of further research and awareness regarding arboviruses of public health concern.
The increasing occurrence of multidrug-resistant (MDR) extended-spectrum β-lactamase- (ESBL) and/or AmpC β-lactamase-producing Enterobacteriaceae in health care systems, the environment and fresh ...produce is a serious concern globally. Production practices, processing and subsequent consumption of contaminated raw fruit and vegetables represent a possible human transmission route. The purpose of this study was to determine the presence of ESBL/AmpC-producing Enterobacteriaceae in complete spinach supply chains and to characterize the isolated strains phenotypically (antimicrobial resistance profiles) and genotypically (ESBL/AmpC genetic determinants, detection of class 1, 2, and 3 integrons). Water, soil, fresh produce, and contact surface samples (
= 288) from two commercial spinach production systems were screened for ESBL/AmpC-producing Enterobacteriaceae. In total, 14.58% (42/288) of the samples were found to be contaminated after selective enrichment, plating onto chromogenic media and matrix-assisted laser desorption ionization time-of-flight mass spectrometry identity confirmation of presumptive ESBL/AmpC isolates. This included 15.28% (11/72) water and 12.12% (16/132) harvested- and processed spinach, while 25% (15/60) retail spinach samples were found to be contaminated with an increase in isolate abundance and diversity in both scenarios. Dominant species identified included
(45.86%),
(20.83%), and
(18.75%). In total, 48 (81.36%) isolates were phenotypically confirmed as ESBL/AmpC-producing Enterobacteriaceae of which 98% showed a MDR phenotype. Genotypic characterization (PCR of ESBL/AmpC resistance genes and integrons) further revealed the domination of the CTX-M Group 1 ESBL type, followed by TEM and SHV; whilst the CIT-type was the only plasmid-mediated AmpC genetic determinant detected. Integrons were detected in 79.17% (
= 38) of the confirmed ESBL/AmpC-producing isolates, of which we highlight the high prevalence of class 3 integrons, detected in 72.92% (
= 35) of the isolates, mostly in
. Class 2 integrons were not detected in this study. This is the first report on the prevalence of ESBL/AmpC-producing Enterobacteriaceae isolated throughout commercial spinach production systems harboring class 1 and/or class 3 integrons in Gauteng Province, South Africa. The results add to the global knowledge base regarding the prevalence and characteristics of ESBL/AmpC-producing Enterobacteriaceae in fresh vegetables and the agricultural environment required for future risk analysis.
About 388 million school‐going children worldwide benefit from school feeding schemes, which make use of fresh produce to prepare meals. Fresh produce including leafy greens and other vegetables were ...served at 37% and 31% of school feeding programs, respectively, in Africa. This study aimed at assessing the microbiological quality of fresh produce grown onsite or supplied to South African schools that are part of the national school feeding programs that benefit over 9 million school‐going children. Coliforms, Escherichia coli, Enterobacteriaceae, and Staphylococcus aureus were enumerated from fresh produce (n = 321) samples. The occurrence of E. coli, Listeria monocytogenes, Salmonella spp., and extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacteriaceae was determined. Presumptive pathogens were tested for antimicrobial resistance. E. coli was further tested for diarrheagenic virulence genes. Enterobacteriaceae on 62.5% of fresh produce samples (200/321) exceeded previous microbiological guidelines for ready‐to‐eat food, while 86% (276/321 samples) and 31.6% (101/321 samples) exceeded coliform and E. coli criteria, respectively. A total of 76 Enterobacteriaceae were isolated from fresh produce including E. coli (n = 43), Enterobacter spp. (n = 15), and Klebsiella spp. (n = 18). Extended‐spectrum β‐lactamase production was confirmed in 11 E. coli, 13 Enterobacter spp., and 17 Klebsiella spp. isolates. No diarrheagenic virulence genes were detected in E. coli isolates. However, multidrug resistance (MDR) was found in 60.5% (26/43) of the E. coli isolates, while all (100%; n = 41) of the confirmed ESBL and AmpC Enterobacteriaceae showed MDR. Our study indicates the reality of the potential health risk that contaminated fresh produce may pose to school‐going children, especially with the growing food safety challenges and antimicrobial resistance crisis globally. This also shows that improved food safety approaches to prevent foodborne illness and the spread of foodborne pathogens through the food served by school feeding schemes are necessary.
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