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Transcutaneous carbon dioxide measurement (TcCO.sub.2) offers the ability to continuously and non-invasively monitor carbon dioxide (CO.sub.2) tensions when end-tidal monitoring is not possible. The accuracy of TcCO.sub.2 has not been established in anesthetized apneic patients with obesity. In this secondary publication, we present a methods comparison analysis of TcCO.sub.2 with the gold standard arterial PCO.sub.2, in adult patients with body mass index (BMI) > 35kg/m.sup.2 who were randomized to receive high flow or low flow nasal oxygenation during post-induction apnea. Agreement between PaCO.sub.2 and TcCO.sub.2 at baseline, the start of apnea and the end of apnea were assessed using a non-parametric difference plot. Forty-two participants had a median (IQR) BMI of 52 (40-58.5) kg/m.sup.2. The mean (SD) PaCO.sub.2 was 33.9 (4.0) mmHg at baseline and 51.4 (7.5) mmHg at the end of apnea. The bias was the greatest at the end of apnea median (95% CI, 95% limits of agreement) 1.90 mmHg (-2.64 to 6.44, -7.10 to 22.90). Findings did not suggest significant systematic differences between the PaCO.sub.2 and TcCO.sub.2 measures. For a short period of apnea, TcCO.sub.2 showed inadequate agreement with PaCO.sub.2 in patients with BMI > 35 kg/m.sup.2. These techniques require comparison in a larger population, with more frequent sampling and over a longer timeframe, before TcCO.sub.2 can be confidently recommended in this setting., Author(s): Victoria A. Eley [sup.1] [sup.2] [sup.4], Louis Guy [sup.1] [sup.2], Christine Woods [sup.1], Stacey Llewellyn [sup.3], Andre A. J. Van Zundert [sup.1] [sup.2] Author Affiliations: (1) https://ror.org/05p52kj31, grid.416100.2, 0000 [...]

Background: Pregnant patients with obesity may have compromised noninvasive blood pressure (NIBP) measurement. We assessed the accuracy and trending ability of the ClearSight™ finger cuff (FC) with invasive arterial monitoring (INV) and arm NIBP, in obese patients having cesarean delivery. Methods: Participants were aged ≥18 years, ≥34 weeks gestation, and body mass index (BMI) ≥ 40 kg m−2. FC, INV, and NIBP measurements were obtained across 5‐min intervals. The primary outcome was agreement of FC measurements with those of the reference standard INV, using modified Bland–Altman plots. Secondary outcomes included comparisons between FC and NIBP and NIBP versus INV, with four‐quadrant plots performed to report discordance rates and evaluate trending ability. Results: Twenty‐three participants had a median (IQR) BMI of 45 kg m−2 (44–48). When comparing FC and INV the mean bias (SD, 95% limits of agreement) for systolic blood pressure (SBP) was 16 mmHg (17, −17.3 to 49.3 mmHg), for diastolic blood pressure (DBP) −0.2 mmHg (10.5, −20.7 to 20.3), and for mean arterial pressure (MAP) 5.2 mmHg (11.1, −16.6 to 27.0 mmHg). Discordance occurred in 54 (26%) pairs for SBP, 41 (23%) for DBP, and 41 (21.7%) for MAP. Error grid analysis showed 92.1% of SBP readings in Zone A (no‐risk zone). When comparing NIBP and INV, the mean bias (95% limits of agreement) for SBP was 13.0 mmHg (16.7, −19.7 to 29.3), for DBP 5.9 mmHg (11.9, −17.4 to 42.0), and for MAP 8.2 mmHg (11.9, −15.2 to 31.6). Discordance occurred in SBP (84 of 209, 40.2%), DBP (74 of 187, 39.6%), and MAP (63 of 191, 33.0%). Conclusions: The FC and NIBP techniques were not adequately in agreement with INV. Trending capability was better for FC than NIBP. Clinically important differences may occur in the setting of the perfusion‐dependent fetus. [ABSTRACT FROM AUTHOR]

Transcutaneous carbon dioxide measurement (TcCO2) offers the ability to continuously and non-invasively monitor carbon dioxide (CO2) tensions when end-tidal monitoring is not possible. The accuracy of TcCO2 has not been established in anesthetized apneic patients with obesity. In this secondary publication, we present a methods comparison analysis of TcCO2 with the gold standard arterial PCO2, in adult patients with body mass index (BMI) > 35kg/m2 who were randomized to receive high flow or low flow nasal oxygenation during post-induction apnea. Agreement between PaCO2 and TcCO2 at baseline, the start of apnea and the end of apnea were assessed using a non-parametric difference plot. Forty-two participants had a median (IQR) BMI of 52 (40–58.5) kg/m2. The mean (SD) PaCO2 was 33.9 (4.0) mmHg at baseline and 51.4 (7.5) mmHg at the end of apnea. The bias was the greatest at the end of apnea median (95% CI, 95% limits of agreement) 1.90 mmHg (−2.64 to 6.44, −7.10 to 22.90). Findings did not suggest significant systematic differences between the PaCO2 and TcCO2 measures. For a short period of apnea, TcCO2 showed inadequate agreement with PaCO2 in patients with BMI > 35 kg/m2. These techniques require comparison in a larger population, with more frequent sampling and over a longer timeframe, before TcCO2 can be confidently recommended in this setting. [ABSTRACT FROM AUTHOR]

Introduction: There is a lack of international consensus as to whether high‐ or low‐level disinfection (HLD or LLD) is required for ultrasound (US) transducers used during percutaneous procedures. This study compared the effectiveness of LLD to HLD on US transducers contaminated with microorganisms from skin. Methods: Two identical linear US transducers repeatedly underwent either LLD or HLD during the study. Randomization determined which of these transducers was applied to left and right forearms of each participant. Swabs taken from transducers before and after reprocessing were plated then incubated for 4–5 days, after which colony forming units (CFU) were counted and identified. The primary hypothesis was the difference in the proportion of US transducers having no CFUs remaining after LLD and HLD would be less than or equal to the noninferiority margin of −5%. Results: Of the 654 recruited participants 73% (n = 478) had microbial growth from both transducers applied to their left and right forearms before reprocessing. These were included in the paired noninferiority statistical analysis where, after disinfection, all CFUs were eliminated in 100% (95% CI: 99.4–100.0%) of HLD transducer samples (n = 478) and 99.0% (95% CI: 97.6–99.7%) of LLD transducer samples (n = 473). The paired difference in the proportion of transducers having all CFUs eliminated between LLD and HLD was −1.0% (95% CI: −2.4 to −0.2%, P‐value <.001). Conclusions: Disinfection with LLD is noninferior to HLD when microorganisms from skin have contaminated the transducer. Therefore, using LLD for US transducers involved in percutaneous procedures would present no higher infection risk compared with HLD. [ABSTRACT FROM AUTHOR]

Background The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)–deficient individuals. Methods Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Results Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. Conclusions Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976). [ABSTRACT FROM AUTHOR]

Background Blocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low-dose tafenoquine. Methods Healthy adults were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50-mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays predose and at 1, 4, and 7 days postdose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia after tafenoquine and safety parameters. Results Six participants were enrolled, and all were infective to mosquitoes before tafenoquine, with a median 86% (range, 22–98) of mosquitoes positive for oocysts and 57% (range, 4–92) positive for sporozoites. By day 4 after tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (interquartile range [IQR]: 16–46) and 52% (IQR: 40–62), respectively, and by day 7, 81% (IQR 36–92) and 77% (IQR 52–98), respectively. The decline in gametocyte density after tafenoquine was not significant. No significant participant safety concerns were identified. Conclusions Low-dose tafenoquine (50 mg) reduces P. falciparum transmission to mosquitoes, with a delay in effect. [ABSTRACT FROM AUTHOR]

Background and Objectives: The 'loss of resistance' technique is used to determine entry into the epidural space, often by a midline needle in the interspinous ligament before the ligamentum flavum. Anatomical explanations for loss of resistance without entry into the epidural space are lacking. This investigation aimed to improve morphometric characterization of the lumbar interspinous ligament by observation and measurement at dissection and from MRI.Methods: Measurements were made on 14 embalmed donor lumbar spines (T12 to S1) imaged with MRI and then dissected along a tilted axial plane aligned with the lumbar interspace.Results: In 73 interspaces, median (IQR) lumbar interspinous plus supraspinous ligament length was 29.7 mm (25.5-33.4). Posterior width was 9.2 mm (7.7, 11.9), with narrowing in the middle (4.5 mm (3.0, 6.8)) and an anterior width of 7.3 mm (5.7, 9.8).Fat-filled gaps were present within 55 (75%). Of 51 anterior gaps, 49 (67%) were related to the ligamenta flava junction. Median (IQR) gap length and width were 3.5 mm (2.5, 5.1) and 1.1 mm (0.9, 1.7).Detection of gaps with MRI had 100% sensitivity (95% CI 93.5 to 100), 94.4% specificity (72.7, 99.9), 98.2% (90.4, 100) positive predictive value and 100% (80.5, 100) negative predictive value against dissection as the gold standard.Conclusions: The lumbar interspinous ligament plus supraspinous ligament are biconcave axially. It commonly has fat-filled gaps, particularly anteriorly. These anatomical features may form the anatomical basis for false or equivocal loss of resistance. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminths (STH) infect up to one-quarter of the global population, with a significant associated disease burden. The main human STH are: Ancylostoma spp. and Necator americanus (hookworms); Ascaris lumbricoides, Trichuris trichiura, and Strongyloides stercoralis. The aim of this study was to establish a scalable system for stool STH multiplex quantitative real-time polymerase chain reactions (qPCR). Stool samples collected in Fiji and preserved in potassium dichromate were transferred to Melbourne at ambient temperature. Samples were washed to remove potassium dichromate and DNA was extracted with the Mini-Beadbeater-24 and a column-based kit. A SYBR green qPCR to detect the vertebrate mitochondrial gene was used as a DNA extraction control. Samples were tested using a probe-based multiplex qPCR targeting A. lumbricoides, T. trichiura and S. stercoralis, and in a second multiplex reaction to detect hookworms to the species level (A. duodenale, A. ceylanicum, N. americanus). An internal amplification control in both multiplex assays was included to prevent false-negative results due to PCR inhibitors. Samples were homogenised for a single cycle of 40 seconds to release STH DNA and washed stool was stored for up to 15 weeks at -30°C without compromising DNA. Our multiplex qPCR detected multiple species of STH without reduced sensitivity compared to singleplex. qPCR data from 40 stools was validated against STH-positive stools determined by microscopy. We have developed and validated an efficient and staged system for detecting six clinically important STH affecting humans that could be easily implemented without advanced automation in any qPCR-capable laboratory. [ABSTRACT FROM AUTHOR]

Purpose: Hypophosphatemia is reported in up to 5% of hospitalized patients and ranges from 20% to 80% in critically ill patients. The consequences of hypophosphatemia for critically ill patients remain controversial. We evaluated the effect of hypophosphatemia on mortality and length of stay in intensive care unit (ICU) patients. Methods: MEDLINE, EMBASE, Cochrane Library (Reviews and Trials), and PubMed were searched for articles in English. The primary outcome was mortality and secondary outcome was length of stay. The quality of evidence was graded using a modified Newcastle-Ottawa Scale. Results: Our search yielded 828 articles and ultimately included 12 studies with 7626 participants in the analysis. Hypophosphatemia was associated with increased hospital length of stay (2.19 days [95% CI, 1.74-2.64]) and ICU length of stay (2.22 days [95% CI, 1.00-3.44]) but not mortality (risk ratio: 1.13 [95% CI, 0.98-1.31]; P = .09). Conclusions: Hypophosphatemia in ICU was associated with increased hospital and ICU length of stay but not all-cause mortality. Hypophosphatemia appears to be a marker of disease severity. Limited number of available studies and varied study designs did not allow for the ascertainment of the effect of severe hypophosphatemia on patient mortality. [ABSTRACT FROM AUTHOR]

Background: New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. Methods: The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results: The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion: The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134 [ABSTRACT FROM AUTHOR]

Background: Molecular-based surveys have indicated that Ancylostoma ceylanicum, a zoonotic hookworm, is likely the second most prevalent hookworm species infecting humans in Asia. Most current PCR-based diagnostic options for the detection of Ancylostoma species target the Internal Transcribed Spacer (ITS) regions of the ribosomal gene cluster. These regions possess a considerable degree of conservation among the species of this genus and this conservation can lead to the misidentification of infecting species or require additional labor for accurate species-level determination. We have developed a novel, real-time PCR-based assay for the sensitive and species-specific detection of A. ceylanicum that targets a non-coding, highly repetitive genomic DNA element. Comparative testing of this PCR assay with an assay that targets ITS sequences was conducted on field-collected samples from Argentina and Timor-Leste to provide further evidence of the sensitivity and species-specificity of this assay. Methods/Principal findings: A previously described platform for the design of primers/probe targeting non-coding highly repetitive regions was used for the development of this novel assay. The assay’s limits of detection (sensitivity) and cross-reactivity with other soil-transmitted helminth species (specificity) were assessed with real-time PCR experiments. The assay was successfully used to identify infections caused by A. ceylanicum that were previously only identified to the genus level as Ancylostoma spp. when analyzed using other published primer-probe pairings. Further proof of sensitive, species-specific detection was provided using a published, semi-nested restriction fragment length polymorphism-PCR assay that differentiates between Ancylostoma species. Conclusions/Significance: Due to the close proximity of people and domestic/wild animals in many regions of the world, the potential for zoonotic infections is substantial. Sensitive tools enabling the screening for different soil-transmitted helminth infections are essential to the success of mass deworming efforts and facilitate the appropriate interpretation of data. This study describes a novel, species-specific, real-time PCR-based assay for the detection of A. ceylanicum that will help to address the need for such tools in integrated STH deworming programs. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: In Timor-Leste there have been intermittent and ineffective soil-transmitted helminth (STH) deworming programs since 2004. In a resource-constrained setting, having information on the geographic distribution of STH can aid in prioritising high risk communities for intervention. This study aimed to quantify the environmental risk factors for STH infection and to produce a risk map of STH in Manufahi district, Timor-Leste. Methodology/Principal findings: Georeferenced cross-sectional data and stool samples were obtained from 2,194 participants in 606 households in 24 villages in the Manufahi District as part of cross sectional surveys done in the context of the “WASH for Worms” randomised controlled trial. Infection status was determined for Ascaris lumbricoides and Necator americanus using real-time quantitative polymerase chain reaction. Baseline infection data were linked to environmental data obtained for each household. Univariable and multivariable multilevel mixed-effects logistic regression analysis with random effects at the village and household level were conducted, with all models adjusted for age and sex. For A. lumbricoides, being a school-aged child increased the odds of infection, whilst higher temperatures in the coolest quarter of the year, alkaline soils, clay loam/loam soils and woody savannas around households were associated with decreased infection odds. For N. americanus, greater precipitation in the driest month, higher average enhanced vegetation index, age and sandy loam soils increased infection odds, whereas being female and living at higher elevations decreased the odds of infection. Predictive risk maps generated for Manufahi based upon these final models highlight the high predicted risk of N. americanus infection across the district and the more focal nature of A. lumbricoides infection. The predicted risk of any STH infection is high across the entire district. Conclusions/Significance: The widespread predicted risk of any STH infection in 6 to 18 year olds provides strong evidence to support strategies for control across the entire geographical area. As few studies include soil texture and pH in their analysis, this study adds to a growing body of evidence suggesting these factors influence STH infection distribution. This study also further supports that A. lumbricoides prefers acidic soils, highlighting a potential relatively unexplored avenue for control. Trial registration: ClinicalTrials.gov . [ABSTRACT FROM AUTHOR]

Background: Timor-Leste has a high prevalence of soil-transmitted helminth (STH) infections. High proportions of the population have been reported as being anaemic, and extremely high proportions of children as stunted or wasted. There have been no published analyses of the contributions of STH to these morbidity outcomes in Timor-Leste. Methods: Using baseline cross-sectional data from 24 communities (18 communities enrolled in a cluster randomised controlled trial, and identically-collected data from six additional communities), analyses of the association between STH infections and community haemoglobin and child development indices were undertaken. Stool samples were assessed for STH using qPCR and participant haemoglobin, heights and weights were measured. Questionnaires were administered to collect demographic and socioeconomic data. Intensity of infection was categorised using correlational analysis between qPCR quantification cycle values and eggs per gram of faeces equivalents, with algorithms generated from seeding experiments. Mixed-effects logistic and multinomial regression were used to assess the association between STH infection intensity classes and anaemia, and child stunting, wasting and underweight. Results: Very high stunting (60%), underweight (60%), and wasting (20%) in children, but low anaemia prevalence (15%), were found in the study communities. STH were not significantly associated with morbidity outcomes. Male children and those in the poorest socioeconomic quintile were significantly more likely to be moderately and severely stunted. Male children were significantly more likely than female children to be severely underweight. Increasing age was also a risk factor for being underweight. Few risk factors emerged for wasting in these analyses. Conclusions: According to World Health Organization international reference standards, levels of child morbidity in this population constitute a public health emergency, although the international reference standards need to be critically evaluated for their applicability in Timor-Leste. Strategies to improve child development and morbidity outcomes, for example via nutrition and iron supplementation programmes, are recommended for these communities. Despite the apparent lack of an association from STH in driving anaemia, stunting, wasting and underweight, high endemicity suggests a need for STH control strategies. [ABSTRACT FROM AUTHOR]

Background: No investigations have been undertaken of risk factors for intensity of soil-transmitted helminth (STH) infection in Timor-Leste. This study provides the first analysis of risk factors for intensity of STH infection, as determined by quantitative PCR (qPCR), examining a broad range of water, sanitation and hygiene (WASH) and environmental factors, among communities in Manufahi District, Timor-Leste. Methods: A baseline cross-sectional survey of 18 communities was undertaken as part of a cluster randomised controlled trial, with additional identically-collected data from six other communities. qPCR was used to assess STH infection from stool samples, and questionnaires administered to collect WASH, demographic, and socioeconomic data. Environmental information was obtained from open-access sources and linked to infection outcomes. Mixed-effects multinomial logistic regression was undertaken to assess risk factors for intensity of Necator americanus and Ascaris infection. Results: 2152 participants provided stool and questionnaire information for this analysis. In adjusted models incorporating WASH, demographic and environmental variables, environmental variables were generally associated with infection intensity for both N. americanus and Ascaris spp. Precipitation (in centimetres) was associated with increased risk of moderate-intensity (adjusted relative risk [ARR] 6.1; 95% confidence interval [CI] 1.9–19.3) and heavy-intensity (ARR 6.6; 95% CI 3.1–14.1) N. americanus infection, as was sandy-loam soil around households (moderate-intensity ARR 2.1; 95% CI 1.0–4.3; heavy-intensity ARR 2.7; 95% CI 1.6–4.5; compared to no infection). For Ascaris, alkaline soil around the household was associated with reduced risk of moderate-intensity infection (ARR 0.21; 95% CI 0.09–0.51), and heavy-intensity infection (ARR 0.04; 95% CI 0.01–0.25). Few WASH risk factors were significant. Conclusion: In this high-prevalence setting, strong risk associations with environmental factors indicate that anthelmintic treatment alone will be insufficient to interrupt STH transmission, as conditions are favourable for ongoing environmental transmission. Integrated STH control strategies should be explored as a priority. [ABSTRACT FROM AUTHOR]

Background: The soil transmitted helminths are a group of parasitic worms responsible for extensive morbidity in many of the world’s most economically depressed locations. With growing emphasis on disease mapping and eradication, the availability of accurate and cost-effective diagnostic measures is of paramount importance to global control and elimination efforts. While real-time PCR-based molecular detection assays have shown great promise, to date, these assays have utilized sub-optimal targets. By performing next-generation sequencing-based repeat analyses, we have identified high copy-number, non-coding DNA sequences from a series of soil transmitted pathogens. We have used these repetitive DNA elements as targets in the development of novel, multi-parallel, PCR-based diagnostic assays. Methodology/Principal Findings: Utilizing next-generation sequencing and the Galaxy-based RepeatExplorer web server, we performed repeat DNA analysis on five species of soil transmitted helminths (Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Ascaris lumbricoides, and Strongyloides stercoralis). Employing high copy-number, non-coding repeat DNA sequences as targets, novel real-time PCR assays were designed, and assays were tested against established molecular detection methods. Each assay provided consistent detection of genomic DNA at quantities of 2 fg or less, demonstrated species-specificity, and showed an improved limit of detection over the existing, proven PCR-based assay. Conclusions/Significance: The utilization of next-generation sequencing-based repeat DNA analysis methodologies for the identification of molecular diagnostic targets has the ability to improve assay species-specificity and limits of detection. By exploiting such high copy-number repeat sequences, the assays described here will facilitate soil transmitted helminth diagnostic efforts. We recommend similar analyses when designing PCR-based diagnostic tests for the detection of other eukaryotic pathogens. [ABSTRACT FROM AUTHOR]

Background: Accurate quantitative assessment of infection with soil transmitted helminths and protozoa is key to the interpretation of epidemiologic studies of these parasites, as well as for monitoring large scale treatment efficacy and effectiveness studies. As morbidity and transmission of helminth infections are directly related to both the prevalence and intensity of infection, there is particular need for improved techniques for assessment of infection intensity for both purposes. The current study aimed to evaluate two multiplex PCR assays to determine prevalence and intensity of intestinal parasite infections, and compare them to standard microscopy. Methodology/Principal Findings: Faecal samples were collected from a total of 680 people, originating from rural communities in Timor-Leste (467 samples) and Cambodia (213 samples). DNA was extracted from stool samples and subject to two multiplex real-time PCR reactions the first targeting: Necator americanus, Ancylostoma spp., Ascaris spp., and Trichuris trichiura; and the second Entamoeba histolytica, Cryptosporidium spp., Giardia. duodenalis, and Strongyloides stercoralis. Samples were also subject to sodium nitrate flotation for identification and quantification of STH eggs, and zinc sulphate centrifugal flotation for detection of protozoan parasites. Higher parasite prevalence was detected by multiplex PCR (hookworms 2.9 times higher, Ascaris 1.2, Giardia 1.6, along with superior polyparasitism detection with this effect magnified as the number of parasites present increased (one: 40.2% vs. 38.1%, two: 30.9% vs. 12.9%, three: 7.6% vs. 0.4%, four: 0.4% vs. 0%). Although, all STH positive samples were low intensity infections by microscopy as defined by WHO guidelines the DNA-load detected by multiplex PCR suggested higher intensity infections. Conclusions/Significance: Multiplex PCR, in addition to superior sensitivity, enabled more accurate determination of infection intensity for Ascaris, hookworms and Giardia compared to microscopy, especially in samples exhibiting polyparasitism. The superior performance of multiplex PCR to detect polyparasitism and more accurately determine infection intensity suggests that it is a more appropriate technique for use in epidemiologic studies and for monitoring large-scale intervention trials. [ABSTRACT FROM AUTHOR]

Background Aim Methods Results Conclusions Central line‐associated bloodstream infections (CLABSIs) are a potential complication for home parenteral nutrition (HPN) patients.We sought to analyse risk factors of developing HPN‐related CLABSI and assess CLABSI management in the Australian context.A retrospective observational cohort study was conducted on 34 adult patients receiving HPN via a central venous catheter (CVC) at a Queensland tertiary referral centre between 2016 and 2023. Patient charts were reviewed, and Kaplan–Meier analysis was employed to determine associations between characteristics and time to CLABSI in the first CVC using Peto‐Peto Prentice test.A total of 39 CLABSI episodes occurred in 19 patients. Patients with ≥1 CLABSI used regular opioids more than those without CLABSI (P = 0.016). Fourteen (41%, n = 14/34) patients developed a CLABSI in their first CVC. No patient or line characteristics were found to be predictive of CLABSI in their first CVC. The CLABSI rate was 1.02/1000 catheter days. Most CLABSIs were caused by Enterobacterales (22%, n = 12/55) and Candida sp. (22%, n = 12/55). Empiric antimicrobial therapy was adequate in only 25% (n = 7/28), and the median time to effective antibiotic therapy was 22.7 h (interquartile range 4.8–29.8). There were three successful CVC salvages (8%, n = 3/39).In this cohort of patients, regular opioid use was associated with increased risk of developing CLABSI. Based on our findings, an empiric antimicrobial regime of vancomycin, cefepime and caspofungin will provide adequate coverage for most HPN‐related CLABSIs in Australian IF units with a similar antimicrobial distribution and resistance pattern. [ABSTRACT FROM AUTHOR]

Background: Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533., Methods: A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia). Part 1 was a double-blind, randomised, placebo-controlled, sequential ascending dose study and part 2 was an open-label, randomised, two-period crossover, pilot food effect study. A phase 1b, open-label, volunteer infection study (VIS) was conducted at Nucleus Network (Herston, QLD, Australia). Eligible participants were adults aged 18-55 years, with a bodyweight of at least 50 kg and BMI of 18-32 kg/m 2 and participants in the VIS were malaria-naive. In part 1 of the FIH study, six cohorts of up to eight participants were randomly assigned (3:1) to a single oral MMV533 dose (5, 10, 20, 50, 100, and 160 mg) or placebo using an automated system, with study staff and participants masked to treatment allocation, and follow-up until day 28. In part 2, MMV533 30 mg was administered open-label to one cohort of nine participants assigned by simple randomisation (1:1) to the fasted-fed (n=4) or fed-fasted (n=5) groups. After a 21-day washout period, fed and fasted groups crossed over with follow-up until day 42. In the VIS, seven participants were assigned using simple randomisation (1:1:1) to three dosing groups of 20 mg (n=3), 35 mg (n=2), or 100 mg (n=2) after parasitaemia was detected, with follow-up until day 28. The primary outcomes were treatment emergent adverse events and relationship to MMV533 for the FIH study assessed in the safety population, and in the VIS primary outcomes were parasite reduction ratio over 48 h (log 10 PRR 48 ), parasite clearance half-life (PCT 1/2 ), and lag phase assessed in the pharmacodynamic population. MMV533 pharmacokinetics was a secondary outcome for both studies, evaluated in the pharmacokinetic population. The studies are registered with ClinicalTrials.gov, NCT04323306 and NCT05205941 (completed)., Findings: The FIH study was conducted between July 31, 2020, and Sept 27, 2022, and the VIS between March 31 and Aug 9, 2022. 335 adults were assessed for eligibility, 71 enrolled, and 69 randomly assigned (53 in part 1 and nine in part 2 of the FIH study, and seven in the VIS). 32 (45%) of 71 participants were female and 39 (55%) were male. In part 1, 24 (63%) of 38 participants had an adverse event after MMV533 administration with no apparent relationship to dose versus six (50%) of 12 after placebo. Treatment-related adverse events were reported for four (11%) participants receiving MMV533 and one (8%) receiving placebo, with no relationship to dose. In part 2, adverse events were reported for three (38%) of eight participants when fasted and four (44%) of nine when fed, with no apparent influence of food. Time to maximum plasma concentration was 4·0-6·0 h, and apparent half-life was 103·8-127·2 h. After a high-fat meal, the geometric mean ratio (fed:fasted) of MMV533 AUC 0-last was 112·0 (90% CI 89·6-140·0). In the VIS for MMV533 100 mg, log 10 PRR 48 was 2·27 (1·99-2·56), PCT 1/2 was 6·36 h (5·64-7·28), and lag phase was 2 h., Interpretation: An acceptable safety and tolerability profile, confirmed parasiticidal activity, and a long half-life support progression of MMV533 into clinical trials in patients with malaria as a component of new antimalarial combination therapies., Funding: MMV Medicines for Malaria Venture and Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests BB, SJ, DL, and SC are employees of MMV. AK, IDR, CB, and AH were employees of MMV at the time of the study. DAF received funding from MMV. DG is the owner and director of Mangareva SRL, which received financial support from MMV to review and interpret the study results. MWM is an employee of ICON, which received funding from MMV. MS is an employee of PharmaKinetic, which received funding from MMV. RAW, SL, and BEB are employees of QIMR Berghofer, which received funding from MMV. PG was an employee of Nucleus Network at the time of the study, which received funding from MMV. JL is an employee of Nucleus Network, which received funding from MMV. VT, DAR, and TY declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There is little information regarding complications of arterial catheterization in modern clinical care. We aimed to determine the incidence of abnormal duplex vascular ultrasound and catheter related infections following perioperative arterial catheterization., Methods: Patients requiring arterial catheterization for elective surgery were included and insertion details collected prospectively. Duplex ultrasound evaluation was performed 24 h after catheter removal. Symptomatic patients were identified by self-reported questionnaire. On Day 7, patients answered questions by telephone, related to the insertion site, pain, and function. Results of catheter tip and blood culture analyses were sought. Univariate associations of patient and surgical characteristics with abnormal ultrasound were assessed with p  < 0.05 considered significant., Results: Of 339 catheterizations, 105 (40%) had ultrasound evaluation. Catheters were indwelling for median (IQR, range) duration of 6.0 h (4.4-8.2, 1.8-28) with no catheter-related infections. There were 16 (15.2%, 95% CI 9.0%-23.6%) abnormal results, including 14 radial artery thromboses, one radial artery dissection, and one radial vein thrombosis. Those with abnormal ultrasound results were more likely to have had Arrow catheters inserted (68.8% vs 27%, p  = 0.023) and more than one skin puncture (37.5% vs 26.8%, p  = 0.031). Two of the 16 (12.5%) patients with abnormal ultrasound results reported new symptoms related to the hand compared with nine of the 88 (10.2%) with normal results ( p  = 0.1). No patients required urgent referral for management., Conclusions: Thrombosis was the most common abnormality and was usually asymptomatic. There were no infections, few post-operative symptoms, and minimal functional impairment following arterial catheterization., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Fujifilm Sonosite Australasia Pty Ltd provided loan equipment for this project (Sonosite Edge II ultrasound machine). CR: My employer (University of Queensland or Griffith University) received unrestricted investigator-initiated research or educational grants on my behalf from 3M, Eloquest, BD, Cardinal Health, and consultancy payments for lectures or expert opinion from 3M, BBraun, and ITL Biomedical. The remaining authors have no other conflicts to declare.

Water, sanitation, and hygiene (WASH) interventions have been proposed as an important complement to deworming programs for sustainable control of soil-transmitted helminth (STH) infections. We aimed to determine whether a community-based WASH program had additional benefits in reducing STH infections compared with community deworming alone. We conducted the WASH for WORMS cluster-randomized controlled trial in 18 rural communities in Timor-Leste. Intervention communities received a WASH intervention that provided access to an improved water source, promoted improved household sanitation, and encouraged handwashing with soap. All eligible community members in intervention and control arms received albendazole every 6 months for 2 years. The primary outcomes were infection with each STH, measured using multiplex real-time quantitative polymerase chain reaction. We compared outcomes between study arms using generalized linear mixed models, accounting for clustering at community, household, and individual levels. At study completion, the integrated WASH and deworming intervention did not have an effect on infection with Ascaris spp. (relative risk [RR] 2.87, 95% confidence interval [CI]: 0.66-12.48, P = 0.159) or Necator americanus (RR 0.99, 95% CI: 0.52-1.89, P = 0.987), compared with deworming alone. At the last follow-up, open defecation was practiced by 66.1% (95% CI: 54.2-80.2) of respondents in the control arm versus 40.2% (95% CI: 25.3-52.6) of respondents in the intervention arm ( P = 0.005). We found no evidence that the WASH intervention resulted in additional reductions in STH infections beyond that achieved with deworming alone over the 2-year trial period. The role of WASH on STH infections over a longer period of time and in the absence of deworming remains to be determined.