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Will Auranofin Become a Golden New Treatment Against COVID-19?

Front Immunol. 2021 Sep 22;12:683694. doi: 10.3389/fimmu.2021.683694. eCollection 2021.

ABSTRACT

Auranofin is an FDA-approved disease-modifying anti-rheumatic drug that has been used for decades for treatment of rheumatoid arthritis. This gold(I) compound has anti-inflammatory properties because it reduces IL-6 expression via inhibition of the NF-κB-IL-6-STAT3 signaling pathway. Also, by inhibiting redox enzymes such as thioredoxin reductase, auranofin increases cellular oxidative stress and promotes apoptosis. Auranofin also possesses antiviral properties. Recently, it was reported that auranofin reduced by 95% SARS-CoV-2 RNA in infected human cells in vitro and decreased SARS-CoV-2-induced cytokine expression, including IL-6. During SARS-CoV-2 infection, a cytokine storm involving IL-6 increases severity of illness and worsens prognosis. Therefore, auranofin could, in our point of view, reduce pathology due to SARS-CoV-2-induced IL-6. COVID-19 is a rapidly-evolving respiratory disease now distributed worldwide. Strikingly high numbers of new COVID-19 cases are reported daily. We have begun a race to vaccinate people, but due to the complex logistics of this effort, the virus will continue to spread before all humans can be immunized, and new variants that may be less well contained by current vaccines are of concern. The COVID-19 pandemic has overwhelmed health care systems and new treatments to reduce mortality are urgently needed. We encourage to further evaluate the potential of auranofin in the treatment of COVID-19 in vitro and in animal models of SARS-CoV-2 infection and, if preliminary data are promising, in clinical trials with COVID-19 patients. In our opinion, auranofin has the potential to become a valuable addition to available therapies in this pandemic.

PMID:34630379 | PMC:PMC8492993 | DOI:10.3389/fimmu.2021.683694

Mining nematode protein secretomes to explain lifestyle and host specificity

PLoS Negl Trop Dis. 2021 Sep 29;15(9):e0009828. doi: 10.1371/journal.pntd.0009828. Online ahead of print.

ABSTRACT

Parasitic nematodes are highly successful pathogens, inflicting disease on humans, animals and plants. Despite great differences in their life cycles, host preference and transmission modes, these parasites share a common capacity to manipulate their host's immune system. This is at least partly achieved through the release of excretory/secretory proteins, the most well-characterized component of nematode secretomes, that are comprised of functionally diverse molecules. In this work, we analyzed published protein secretomes of parasitic nematodes to identify common patterns as well as species-specific traits. The 20 selected organisms span 4 nematode clades, including plant pathogens, animal parasites, and the free-living species Caenorhabditis elegans. Transthyretin-like proteins were the only component common to all adult secretomes; many other protein classes overlapped across multiple datasets. The glycolytic enzymes aldolase and enolase were present in all parasitic species, but missing from C. elegans. Secretomes from larval stages showed less overlap between species. Although comparison of secretome composition across species and life-cycle stages is challenged by the use of different methods and depths of sequencing among studies, our workflow enabled the identification of conserved protein families and pinpointed elements that may have evolved as to enable parasitism. This strategy, extended to more secretomes, may be exploited to prioritize therapeutic targets in the future.

PMID:34587193 | DOI:10.1371/journal.pntd.0009828

Infant Anthropometry and Growth Velocity Before 6 Months are Associated with Breastfeeding Practices and the Presence of Subclinical Mastitis and Maternal Intestinal Protozoa in Indigenous Communities in Guatemala

Curr Dev Nutr. 2021 Sep 16;5(9):nzab086. doi: 10.1093/cdn/nzab086. eCollection 2021 Sep.

ABSTRACT

BACKGROUND: The possibility that maternal health status and breastfeeding practices contribute to growth faltering before 6 mo is underexplored.

OBJECTIVES: This longitudinal study investigated whether indicators of subclinical mastitis (SCM) and breast inflammation, maternal fecal-oral contamination, and/or breastfeeding practices were associated with infant anthropometry or growth velocity before 6 mo.

METHODS: Indigenous Mam-Mayan mother-infant dyads (n = 140) were recruited. Breast milk was collected at early (<6 wk) and established (4-6 mo) lactation when maternal and infant anthropometry were measured. Milk Na:K ratio as an indicator of SCM and concentrations of 4 proinflammatory cytokines were measured. Maternal stool samples were examined for the presence of intestinal parasites including nonpathogenic protozoa (Endolimax nana, Iodamoeba bütschlii, Entamoeba coli, Blastocystis hominis). Questionnaires characterized breastfeeding and hygiene practices. Multiple linear regression identified factors associated with infant growth attainment [weight-for-age z-score (WAZ), length-for-age z-score (LAZ), and head circumference-for-age z-score (HCAZ)] and growth velocity (expressed as change per day from early to established lactation). Multiple logistic regression identified factors associated with increased odds of underweight, stunting, and low head circumference at both lactation stages.

RESULTS: A higher Na:K ratio, individual nonpathogenic protozoa, and specific breastfeeding and hygiene practices were associated with impaired growth before 6 wk and at 4-6 mo in exclusively breastfed infants. Growth velocity for weight was inversely associated with Entamoeba coli but cranial growth was associated positively with Iodamoeba bütschlii whereas feeding colostrum in early lactation was protective and decreased the odds of an HCAZ < -2 SD. Finally, the presence of SCM in early lactation increased the likelihood of both WAZ < -2 SD and LAZ < -2 SD by 6 wk.

CONCLUSIONS: Prevention of SCM can improve early infant weight, but measures that promote the feeding of colostrum and reduce exposure to fecal-oral contamination might be required to minimize infant growth faltering in breastfed infants.

PMID:34585057 | PMC:PMC8460162 | DOI:10.1093/cdn/nzab086

Strongyloidiasis in immunocompromised migrants to non-endemic countries in the era of COVID-19: What is the role for presumptive ivermectin?

J Travel Med. 2021 Sep 28:taab155. doi: 10.1093/jtm/taab155. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has led to widespread use of dexamethasone. Corticosteroid therapy is an important risk factor for Strongyloides hyperinfection. Challenges associated with the performance of Strongyloides tests, and the poor availability of high quality and timely diagnostic testing, makes the use of presumptive ivermectin reasonable in selected situations.

PMID:34581413 | DOI:10.1093/jtm/taab155

The viral hepatitis B care cascade: A population-based comparison of immigrant groups

Hepatology. 2021 Sep 19. doi: 10.1002/hep.32162. Online ahead of print.

ABSTRACT

The global burden of viral hepatitis B is substantial and monitoring infections across the care cascade is important for elimination efforts. There is little information on care disparities by immigration status and we aimed to quantify disease burden among immigrant subgroups. In this population-based retrospective cohort study, we used linked laboratory and health administrative records to describe the HBV care cascade in five distinct stages: 1) lifetime prevalence; 2) diagnosis, 3) engagement with care; 4) treatment initiation; and 5) treatment continuation. Infections were identified based on at least one reactive antigen or nucleic acid test, and lifetime prevalence was estimated as the sum of diagnosed and estimated undiagnosed cases. Care cascades were compared between long-term residents and immigrant groups, including subgroups born in hepatitis B endemic countries. Stratified analyses and multivariable Poisson regression were used to identify drivers for cascade progression. Between January 1997 and December 2014, 2,014,470 individuals were included, 50,475 with infections, of whom 30,118 were engaged with care, 11,450 initiated treatment, and 6,554 continued treatment greater than one year. Lifetime prevalence was estimated as 163,309 (1.34%) overall, 115,722 (3.42%) among all immigrants, and 50,876 (9.37%) among those from highly endemic countries. Compared to long-term residents, immigrants were more likely to be diagnosed (aRR: 4.55 [95%CI: 4.46, 4.63]), engaged with care (aRR: 1.07 [95%CI: 1.04, 1.09]), and initiate treatment (aRR: 1.09 [95%CI: 1.03, 1.16]). In conclusion, immigrants fared well compared to long-term residents along the care cascade, having higher rates of diagnosis and slightly better measures in subsequent cascade stages, although intensified screening efforts and better strategies to facilitate linkage to care are still needed.

PMID:34537985 | DOI:10.1002/hep.32162

Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial

Nat Med. 2021 Sep 9. doi: 10.1038/s41591-021-01488-2. Online ahead of print.

ABSTRACT

The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

PMID:34504336 | DOI:10.1038/s41591-021-01488-2

Promising Technologies in the Field of Helminth Vaccines

Front Immunol. 2021 Aug 19;12:711650. doi: 10.3389/fimmu.2021.711650. eCollection 2021.

ABSTRACT

Helminths contribute a larger global burden of disease than both malaria and tuberculosis. These eukaryotes have caused human infections since before our earliest recorded history (i.e.: earlier than 1200 B.C. for Schistosoma spp.). Despite the prevalence and importance of these infections, helminths are considered a neglected tropical disease for which there are no vaccines approved for human use. Similar to other parasites, helminths are complex organisms which employ a plethora of features such as: complex life cycles, chronic infections, and antigenic mimicry to name a few, making them difficult to target by conventional vaccine strategies. With novel vaccine strategies such as viral vectors and genetic elements, numerous constructs are being defined for a wide range of helminth parasites; however, it has yet to be discussed which of these approaches may be the most effective. With human trials being conducted, and a pipeline of potential anti-helminthic antigens, greater understanding of helminth vaccine-induced immunity is necessary for the development of potent vaccine platforms and their optimal design. This review outlines the conventional and the most promising approaches in clinical and preclinical helminth vaccinology.

PMID:34489961 | PMC:PMC8418310 | DOI:10.3389/fimmu.2021.711650

OPD (Online Plasmodium Diagnosis): An ALA-PpIX based Functional Assay to Predict Active Malaria

Photodiagnosis Photodyn Ther. 2021 Aug 30:102510. doi: 10.1016/j.pdpdt.2021.102510. Online ahead of print.

ABSTRACT

BACKGROUND: Malaria kills one child every 30 seconds reaching up to 3000 children a day. The mosquito borne malarial parasite invades the blood stream and hijacks red blood cells (RBCs). One of the medical successes of the 20th century is development of malaria diagnostic tests. However, poor specificity and sensitivity along with the inability of these assays to distinguish active malarial infections has put the management scheme in jeopardy.

AIM: To develop an in-vitro functional assay to predict active malarial infections METHODS: Plasmodium falciparum (3D7) parasites were incubated with delta-aminolevulinic acid (ALA) for 7 h and imaged using a confocal microscope for protoporphyrin IX (PpIX) fluorescence. Similarly, PpIX was extracted, and fluorescence was estimated by fluorimetry.

RESULTS: Imaging showed that the falciparum-infected RBCs fluoresced while the non-infected cells did not. Moreover, fluorimetry showed fluorescent peaks only in actively infected RBCs.

CONCLUSIONS: ALA was only taken up by infected RBCs. When the parasites were loaded with ALA, they fluoresced. These proof-of-concept results demonstrate the first functional assay to detect/diagnose active malaria.

PMID:34474169 | DOI:10.1016/j.pdpdt.2021.102510

Babesia microti in a Canadian blood donor and lookback in a red blood cell recipient

Vox Sang. 2021 Aug 31. doi: 10.1111/vox.13198. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: We describe the third documented case of autochthonous human babesiosis in Canada and the second in a Canadian blood donor.

MATERIALS AND METHODS: Multiple laboratory investigations were carried out on the donor and the immunocompromised recipient of an associated, potentially infectious red blood cell product.

RESULTS: The donor had not travelled except for outdoor exposure in south-eastern Manitoba, followed by illness and hospital admission. The donor had a notable parasitaemia, positive for Babesia microti using whole blood nucleic acid testing (NAT). The recipient was negative for B. microti by both serology and NAT.

CONCLUSION: There was no evidence of transfusion-transmitted babesiosis.

PMID:34462920 | DOI:10.1111/vox.13198

Single-dose mRNA vaccine effectiveness against SARS-CoV-2 in healthcare workers extending 16 weeks post-vaccination: a test-negative design from Quebec, Canada

Clin Infect Dis. 2021 Aug 30:ciab739. doi: 10.1093/cid/ciab739. Online ahead of print.

ABSTRACT

INTRODUCTION: In Canada, first and second doses of mRNA vaccines against SARS-CoV-2 were uniquely spaced 16 weeks apart, but the duration of single-dose protection remains uncertain. We estimated one- and two-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Quebec, Canada including protection against varying outcome severity, variants of concern (VOC), and the stability of single-dose protection out to 16 weeks post-vaccination.

METHODS: A test-negative design compared vaccination among SARS-CoV-2 test-positive and weekly-matched (10:1), randomly-sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by one dose ≥14 days or two doses ≥7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression.

RESULTS: Primary analysis included 5,316 cases and 53,160 controls. Single-dose VE was 70% (95%CI: 68-73) against SARS-CoV-2 infection, 73% (95%CI: 71-75) against COVID-19 illness and 97% (95%CI: 92-99) against associated hospitalization. Two-dose VE was 86% (95%CI: 81-90) and 93% (95%CI: 89-95), respectively, with no associated hospitalizations. VE was higher for non-VOC than VOC (73% Alpha) among single-dose (77%, 95%CI: 73-81 versus 63%, 95%CI: 57-67) but not two-dose recipients (87%, 95%CI: 57-96 versus 94%, 95%CI: 89-96). Across 16 weeks, no decline in single-dose VE was observed with appropriate stratification based upon prioritized vaccination determined by higher versus lower likelihood of direct patient contact.

CONCLUSION: One mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least four months post-vaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy to consider.

PMID:34460902 | DOI:10.1093/cid/ciab739

Relative effectiveness of influenza vaccines in elderly persons in the United States, 2012/2013-2017/2018 seasons

NPJ Vaccines. 2021 Aug 24;6(1):108. doi: 10.1038/s41541-021-00373-w.

ABSTRACT

Influenza immunization protects seniors against influenza and its potentially serious complications. It is uncertain whether standard-dose (SD) quadrivalent vaccine offers better protection over other formulations in the elderly. In this study, we compared the effectiveness of SD-trivalent, high-dose (HD) trivalent, SD-quadrivalent, and adjuvanted trivalent vaccines in seniors (≥65 years) in a real-world setting. We selected over 200,000 individuals in each of 6 influenza seasons from 2012 to 2018 using MarketScan® databases. The two outcomes were hospitalization or emergency room (ER) visit due to (1) influenza or (2) pneumonia. Here, SD-quadrivalent was associated with higher risk of influenza-related hospitalization/ER visit (adjusted hazard ratio (aHR) 1.14 and 95% confidence interval (95% CI) 1.05-1.24) and of pneumonia-related hospitalization/ER visit (aHR 1.04 and 95% CI 1.01-1.07) vs. HD-trivalent. SD-trivalent followed similar trends compared to HD-trivalent (aHR 1.16 and 95% CI 1.06-1.27 for hospitalized/ER visit influenza; aHR 1.07 and 95% CI 1.05-1.10 for hospitalized/ER visit pneumonia). We could not demonstrate risk differences between SD vaccine formulations and between adjuvanted trivalent and one of the other three vaccines. Risk estimates slightly varied across seasons. These findings suggest that SD vaccine formulations vs. HD-trivalent were associated with higher risk of hospitalization/ER visit for influenza and pneumonia in seniors.

PMID:34429431 | DOI:10.1038/s41541-021-00373-w

Therapeutic activity of a Salmonella-vectored Schistosoma mansoni vaccine in a mouse model of chronic infection

Vaccine. 2021 Aug 16:S0264-410X(21)01051-3. doi: 10.1016/j.vaccine.2021.08.031. Online ahead of print.

ABSTRACT

Schistosomiasis is an important fresh-water-borne parasitic disease caused by trematode worms of the genus Schistosoma. With > 250 million people infected worldwide and approximately 800 million people at risk, the World Health Organization considers schistosomiasis to be the most important human helminth infection. Several prophylactic non-living vaccines are in pre-clinical and clinical development, but only one has been assessed for therapeutic effect in an animal model with modest results. Live attenuated Salmonella have multiple potential advantages as vaccine vectors. We have engineered an attenuated Salmonella enterica Typhimurium strain (YS1646) to produce a vaccine that targets the parasite digestive enzyme Cathepsin B (CatB). A multi-modality immunization schedule was used in chronically infected mice that included three oral (PO) doses of this CatB-bearing YS1646 strain on days one, three, and five as well as an intramuscular (IM) dose of recombinant CatB on day one. Parasite burden (worm count, intestinal and liver egg numbers) were 46.5 - 50.3% lower than in control animals 1 month post-vaccination and relative reductions further increased to 63.9 - 73.3% at 2 months. Serum anti-CatB IgG increased significantly after vaccination with the development of a more balanced TH1/TH2 pattern of response (ie: a shift in the IgG1:IgG2c ratio). Compared to control animals, a broad and robust CatB-specific cytokine/chemokine response was seen in splenocytes isolated 1 month post-vaccination. A vaccine that has both prophylactic and therapeutic activity would be ideal for use in conjunction with mass treatment campaigns with praziquantel in schistosome-endemic countries.

PMID:34412919 | DOI:10.1016/j.vaccine.2021.08.031

Initiation and completion of treatment for latent tuberculosis infection in migrants globally: a systematic review and meta-analysis

Lancet Infect Dis. 2021 Aug 4:S1473-3099(21)00052-9. doi: 10.1016/S1473-3099(21)00052-9. Online ahead of print.

ABSTRACT

BACKGROUND: Latent tuberculosis infection (LTBI) is one of the most prevalent infections globally and can lead to the development of active tuberculosis disease. In many low-burden countries, LTBI is concentrated within migrant populations often because of a higher disease burden in the migrant's country of origin. National programmes consequently focus on screening and treating LTBI in migrants to prevent future tuberculosis cases; however, how effective these programmes are is unclear. We aimed to assess LTBI treatment initiation and outcomes among migrants, and the factors that influence both.

METHODS: For this systematic review and meta-analysis, we searched Embase, MEDLINE, and Global Health, and manually searched grey literature from Jan 1, 2000, to April 21, 2020. We included primary research articles reporting on LTBI treatment initiation or completion, or both, in migrants and excluded articles in which data were not stratified by migrant status, or in which the data were related to outcomes before 2000. There were no geographical or language restrictions. All included studies were quality appraised using recognised tools depending on their design, and we assessed the heterogeneity of analyses using I2. We extracted data on the numbers of migrants initiating and completing treatment. Our primary outcomes were LTBI treatment initiation and completion in migrants (defined as foreign-born). We used random-effects meta-regression to examine the influence of factors related to these outcomes. The study is registered with PROSPERO (CRD42019140338).

FINDINGS: 2199 publications were retrieved screened, after which 39 publications from 13 mostly high-income, low-burden countries were included in our analyses, with treatment initiation and completion data reported for 31 598 migrants positive for LTBI, with not all articles reporting the full pathway from initiation to completion. The pooled estimate for the true proportion of migrants testing positive who initiated treatment was 69% (95% CI 51-84; I2= 99·62%; 4409 of 8764). The pooled estimate for the true proportion of migrants on treatment in datasets, who subsequently completed it was 74% (95% CI = 66-81; I2= 99·19%; 15 516 of 25 629). Where data were provided for the entire treatment pathway, the pooled estimate for the true proportion of migrants who initiated and completed treatment after a positive test was only 52% (95% CI 40-64; I2= 98·90%; 3289 of 6652). Meta-regression showed that LTBI programmes are improving, with more recent reported data (2010-20) associated with better rates of treatment initiation and completion, with multiple complex factors affecting treatment outcomes in migrants.

INTERPRETATION: Although our analysis highlights that LTBI treatment initiation and completion in migrants has improved considerably from 2010-20, there is still room for improvement, with drop out reported along the entire treatment pathway. The delivery of these screening and treatment programmes will require further strengthening if the targets to eradicate tuberculosis in low-incidence countries are to be met, with greater focus needed on engaging migrants more effectively in the clinic and understanding the diverse and unique barriers and facilitators to migrants initiating and completing treatment.

FUNDING: European Society of Clinical Microbiology and Infectious Diseases, the Rosetrees Trust, the National Institute for Health Research, and the Academy of Medical Sciences.

PMID:34363771 | DOI:10.1016/S1473-3099(21)00052-9

Treatment strategies for Nitroimidazole-refractory giardiasis: A systematic review

J Travel Med. 2021 Aug 5:taab120. doi: 10.1093/jtm/taab120. Online ahead of print.

ABSTRACT

Rationale for review: Giardiasis is one of the most common human protozoal infections worldwide. First line therapy of giardiasis includes nitroimidazole antibiotics. However, treatment failure with nitroimidazoles is increasingly reported with up to 45% of patients not responding to initial treatment. There is no clear consensus on the approach to the management of nitroimidazole refractory giardiasis. This systematic review aims to summarize the literature on pharmacotherapy for nitroimidazole refractory giardiasis.

METHODS: We conducted a systematic review of the literature to determine the optimal management strategies for nitroimidazole refractory giardiasis. We searched Pubmed/MEDLINE, Embase, and Cochrane library using the following search terms 'Giardia' AND 'treatment failure' OR 'refractory giardia' OR 'resistant giardia' with date limits of January 1, 1970 to June 30, 2021. We included all reports on humans which described clinical outcomes of individuals with treatment refractory giardiasis, including case series and case reports. A descriptive synthesis of the data was conducted with pooling of data for interventions.

KEY FINDINGS: Included in this review were 5 prospective studies, 3 retrospective studies, 7 case series and 9 case reports. Across these reports, a wide heterogeneity of treatment regimens was employed, including re-treatment with an alternative nitroimidazole, combination therapy with a nitroimidazole and another agent, and monotherapy with non-nitroimidazole regimens including quinacrine, paromomycin and nitazoxanide. Retreatment with a nitroimidazole was not an effective therapy for refractory giardiasis. However, treatment with a nitroimidazole in combination with albendazole had a cure rate of 66.9%. In the included studies, quinacrine monotherapy was administered to a total of 179 patients with a clinical cure rate of 88.8%. Overall, quinacrine was fairly well tolerated.

CONCLUSIONS: Reports on the treatment of nitroimidazole refractory giardiasis demonstrate a heterogeneous approach to treatment. Of these, quinacrine appeared to be highly effective though more data on its safety is needed.

PMID:34350966 | DOI:10.1093/jtm/taab120

Neither Blood Culture Positivity nor Time to Positivity Is Associated With Mortality Among Patients Presenting With Severe Manifestations of Sepsis: The FABLED Cohort Study

Open Forum Infect Dis. 2021 Jun 17;8(7):ofab321. doi: 10.1093/ofid/ofab321. eCollection 2021 Jul.

ABSTRACT

BACKGROUND: Sepsis is a leading cause of morbidity, mortality, and health care costs worldwide.

METHODS: We conducted a multicenter, prospective cohort study evaluating the yield of blood cultures drawn before and after empiric antimicrobial administration among adults presenting to the emergency department with severe manifestations of sepsis. Enrolled patients who had the requisite blood cultures drawn were followed for 90 days. We explored the independent association between blood culture positivity and its time to positivity in relation to 90-day mortality.

RESULTS: Three hundred twenty-five participants were enrolled; 90-day mortality among the 315 subjects followed up was 25.4% (80/315). Mortality was associated with age (mean age [standard deviation] in those who died was 72.5 [15.8] compared with 62.9 [17.7] years among survivors; P < .0001), greater Charlson Comorbidity Index (2 [interquartile range {IQR}, 1-3] vs 1 [IQR, 0-3]; P = .008), dementia (13/80 [16.2%] vs 18/235 [7.7%]; P = .03), cancer (27/80 [33.8%] vs 47/235 [20.0%]; P = .015), positive quick Sequential Organ Failure Assessment score (57/80 [71.2%] vs 129/235 [54.9%]; P = .009), and normal white blood cell count (25/80 [31.2%] vs 42/235 [17.9%]; P = .02). The presence of bacteremia, persistent bacteremia after antimicrobial infusion, and shorter time to blood culture positivity were not associated with mortality. Neither the source of infection nor pathogen affected mortality.

CONCLUSIONS: Although severe sepsis is an inflammatory condition triggered by infection, its 90-day survival is not influenced by blood culture positivity nor its time to positivity.

CLINICAL TRIALS REGISTRATION: NCT01867905.

PMID:34307728 | PMC:PMC8294679 | DOI:10.1093/ofid/ofab321

Multiplexed technologies for sexually transmitted infections: global evidence on patient-centered and clinical health outcomes

BMJ Glob Health. 2021 Jul;6(7):e005670. doi: 10.1136/bmjgh-2021-005670.

ABSTRACT

INTRODUCTION: Conventional care packages around screening for sexually transmitted infections (STIs) entail multiple clinic visits and precipitate losses to follow-up. To prevent these losses, multiplexed technologies for STIs (immunochromatographic tests/devices/assays and molecular assays that can screen multiple pathogens or multiple strains of one STI) can yield same-day results in a single visit. Research evidence of patient-centred (preference, satisfaction) and clinical health outcomes (feasibility, case positivity, uptake, impact) has not been synthesised. We conducted a systematic review to fill this gap.

METHODS: For the period 2009-2020, two independent reviewers searched PubMed and Embase, retrieved 4440 citations and abstracted data from 42 relevant studies.

RESULTS: Of 42 studies, 10 (23.8%) evaluated multiplexed immunochromatographic and 32 (76.2%) molecular assays. Outcomes were reported as follows: preference (n=3), satisfaction (n=2), uptake (n=1), feasibility (n=2), case positivity (n=42) and impact (n=11). Screened populations included various at-risk groups. A majority (86.1%-92.4%) of participants preferred (60.2%-97.2%) multiplexed technologies (over conventional testing). Compared with conventional lab-based testing, test uptake improved by 99.4% (hepatitis C), 99.6% (Trichomonas vaginalis), 78.6% (hepatitis B) and 42.0% (HIV). Varying case positivities were documented depending on populations screened: HIV (1.8%-29.3%), hepatitis B (1.1%-23.9%), hepatitis C (0.5%-42.2%), Chlamydia trachomatis (2.8%-30.2%), Neisseria gonorrhoeae (0.0%-30.3%) and T. vaginalis (0.0%-32.7%). Regarding impact, 70.0%-100.0% of screened participants were linked to care, with result turnaround times ranging from 14 min (immunochromatographic assays) to 300 min (molecular assays).

CONCLUSIONS: Compared with conventional lab-based testing, rapid multiplexed technologies were preferred by testees and led to quicker turnaround times for many STIs yielding same-day results thereby allowing to initiate rapid linkages to care. They were further shown to be highly feasible and impactful for detection and treatment facilitation. Based on these promising results, multiplexed technologies offer potential to screen at-risk populations to reduce onward STI transmission worldwide.

PMID:34301675 | DOI:10.1136/bmjgh-2021-005670

Using Transcriptomics and Metabolomics to Understand Species Differences in Sensitivity to Chlorpyrifos in Japanese Quail and Double-Crested Cormorant Embryos

Environ Toxicol Chem. 2021 Jul 22. doi: 10.1002/etc.5174. Online ahead of print.

ABSTRACT

Modern 21st century toxicity testing makes use of omics technologies to address critical questions in toxicology and chemical management. Of interest are questions relating to chemical mechanisms of toxicity, differences in species sensitivity, and translation of molecular effects to observable apical endpoints. Our study addressed these questions by comparing apical outcomes and multiple omics responses in early-life stage exposure studies with Japanese quail (JQ; Coturnix japonica) and double-crested cormorant (DCCO; Phalacrocorax auritus), representing a model and ecological species, respectively. Specifically, we investigated the dose-dependent response of apical outcomes as well as transcriptomics and metabolomics in the liver of each species exposed to chlorpyrifos (CPF), a widely used organophosphate pesticide. Our results revealed a clear pattern of dose-dependent disruption of gene expression and metabolic profiles in JQ but not DCCO at similar CPF exposure concentrations. The difference in sensitivity between species was likely due to higher metabolic transformation of CPF in JQ compared to DCCO. The most impacted biological pathways after CPF exposure in JQ included hepatic metabolism, oxidative stress, endocrine disruption (steroid and non-steroid hormones), and metabolic disease (lipid and fatty acid metabolism). Importantly, we show consistent responses across biological scales, suggesting that significant disruption at the level of gene expression and metabolite profiles leads to observable apical responses at the organism level. Our study demonstrates the utility of evaluating effects at multiple biological levels of organization to understand how modern toxicity testing relates to outomes of regulatory relevance, while also highlighting important, yet poorly understood, species differences in sensitivity to chemical exposure. This article is protected by copyright. All rights reserved.

PMID:34293216 | DOI:10.1002/etc.5174

Development of emodepside as a possible adulticidal treatment for human onchocerciasis-The fruit of a successful industrial-academic collaboration

PLoS Pathog. 2021 Jul 22;17(7):e1009682. doi: 10.1371/journal.ppat.1009682. eCollection 2021 Jul.

ABSTRACT

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer-DNDi partnership is an outstanding example of "One World Health," in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.

PMID:34293063 | DOI:10.1371/journal.ppat.1009682

Assessing the Toxicity of 17α-Ethinylestradiol in Rainbow Trout Using a 4-Day Transcriptomics Benchmark Dose (BMD) Embryo Assay

Environ Sci Technol. 2021 Jul 22. doi: 10.1021/acs.est.1c02401. Online ahead of print.

ABSTRACT

There is an urgent demand for more efficient and ethical approaches in ecological risk assessment. Using 17α-ethinylestradiol (EE2) as a model compound, this study established an embryo benchmark dose (BMD) assay for rainbow trout (RBT; Oncorhynchus mykiss) to derive transcriptomic points-of-departure (tPODs) as an alternative to live-animal tests. Embryos were exposed to graded concentrations of EE2 (measured: 0, 1.13, 1.57, 6.22, 16.3, 55.1, and 169 ng/L) from hatch to 4 and up to 60 days post-hatch (dph) to assess molecular and apical responses, respectively. Whole proteome analyses of alevins did not show clear estrogenic effects. In contrast, transcriptomics revealed responses that were in agreement with apical effects, including excessive accumulation of intravascular and hepatic proteinaceous fluid and significant increases in mortality at 55.1 and 169 ng/L EE2 at later time points. Transcriptomic BMD analysis estimated the median of the 20th lowest geneBMD to be 0.18 ng/L, the most sensitive tPOD. Other estimates (0.78, 3.64, and 1.63 ng/L for the 10th percentile geneBMD, first peak geneBMD distribution, and median geneBMD of the most sensitive over-represented pathway, respectively) were within the same order of magnitude as empirically derived apical PODs for EE2 in the literature. This 4-day alternative RBT embryonic assay was effective in deriving tPODs that are protective of chronic effects of EE2.

PMID:34292719 | DOI:10.1021/acs.est.1c02401

The phenothiazine, trifluoperazine, is selectively lethal to ABCB1-expressing multidrug resistant cells

Biochem Biophys Res Commun. 2021 Jul 16;570:148-153. doi: 10.1016/j.bbrc.2021.07.031. Online ahead of print.

ABSTRACT

P-glycoprotein, member of the B-subfamily of the ATP-binding cassette (ABC) superfamily (e.g., ABCB1), has been demonstrated to confer resistance to clinically relevant anticancer drugs. Paradoxically, ABCB1-expressing multidrug resistant (MDR) cells are hypersensitivity or collateral sensitivity to non-toxic drugs. In this report, we demonstrate the capacity of trifluoperazine (TFP), a calmodulin inhibitor, to confer a collateral sensitivity onto ABCB1-overexpressing MDR cells. We show TFP-induced collateral sensitivity to be linked to ABCB1 expression and ATPase activity, as such phenotype is abolished in ABCB1-knockout MDR cells (CHORC5ΔABCB1 clones A1-A3) or with inhibitors of ABCB1 ATPase. TFP-induced collateral sensitivity is mediated by apoptotic cell death, due to enhanced oxidative stress. The findings in this study show for first time the use TFP as a collateral sensitivity drug, at clinically relevant concentrations. Moreover, given the use of trifluoperazine in the treatment for symptoms of schizophrenia and the role of ABCB1 transporter in tissue blood barriers and other physiologic functions, the finding in this study may have implications beyond cancer chemotherapy.

PMID:34284140 | DOI:10.1016/j.bbrc.2021.07.031

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