Publications by authors named "Charles Goss"

40 Publications

Assessment of serological assays for identifying high titer convalescent plasma.

medRxiv 2021 Mar 28. Epub 2021 Mar 28.

The COVID-19 pandemic has been accompanied by the largest mobilization of therapeutic convalescent plasma (CCP) in over a century. Initial identification of high titer units was based on dose-response data using the Ortho VITROS IgG assay. The proliferation of SARS-CoV-2 serological assays and non-uniform application has led to uncertainty about their interrelationships. The purpose of this study was to establish correlations and analogous cutoffs between commercially available serological tests (Ortho, Abbott, Roche), a spike ELISA, and a virus neutralization assay using convalescent plasma from a cohort of 79 donors from April 2020. Relationships relative to FDA-approved cutoffs under the CCP EUA were identified by linear regression and receiver operator characteristic curves. Relative to the Ortho VITROS assay, the r of the Abbott, Roche, the anti-Spike ELISA and the neutralizing assay were 0.58, 0.5, 0.82, and 0.44, respectively. The best correlative index for establishing high-titer units was 3.82 S/C for the Abbott, 10.89 COI for the Roche, 1:1,202 for the anti-Spike ELISA, and 1:200 by the neutralization assay. The overall agreement using derived cutoffs compared to the CCP EUA Ortho VITROS cutoff of 9.5 was 92.4% for Abbott, 84.8% for Roche, 87.3% for the anti-S ELISA and 78.5% for the neutralization assay. Assays based on antibodies against the nucleoprotein (Roche, Abbott) and neutralizing antibody tests were positively associated with the Ortho assay, although their ability to distinguish FDA high-titer specimens was imperfect. The resulting relationships help reconcile results from the large body of serological data generated during the COVID-19 pandemic.
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http://dx.doi.org/10.1101/2021.03.26.21254427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010743PMC
March 2021

Semiannual Treatment of Albendazole Alone is Efficacious for Treatment of Lymphatic Filariasis: A Randomized Open-label Trial in Cote d'Ivoire.

Clin Infect Dis 2021 Mar 1. Epub 2021 Mar 1.

Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Background: Ivermectin (IVM) plus albendazole (ALB), or IA, is widely used in mass drug administration (MDA) programs that aim to eliminate lymphatic filariasis (LF) in Africa. However, IVM can cause severe adverse events in persons with heavy Loa loa infections that are common in Central Africa. ALB is safe in loiasis, but more information is needed on its efficacy for LF. This study compared the efficacy and safety of three years of semiannual treatment with ALB to annual IA in persons with bancroftian filariasis.

Methods: Adults with Wuchereria bancrofti microfilaremia (Mf) were randomized to receive either three annual doses of IA (N=52), six semiannual doses of ALB 400mg (N=45), or six semiannual doses of ALB 800mg (N=47). The primary outcome amicrofilaremia at 36 months.

Findings: IA was more effective for completely clearing Mf than ALB 400mg or ALB 800mg (79%, CI 67-91; vs. 48%, CI 32-66 and 57%, CI 41-73, respectively). Mean % reductions in Mf counts at 36 months relative to baseline tended to be greater after IA (98%, CI 88-100) than after ALB 400mg (88%, CI 78-98) and ALB 800mg (89%, CI 79-99) (P=0.07 and P=0.06, respectively). Adult worm nest numbers (assessed by ultrasound) were reduced in all treatment groups. Treatments were well tolerated.

Interpretation: Repeated semiannual treatment with ALB is macrofilaricidal for W. bancrofti and leads to sustained reductions in Mf counts. This is a safe and effective regimen that could be used as MDA to eliminate LF in areas ivermectin cannot be used.
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http://dx.doi.org/10.1093/cid/ciab194DOI Listing
March 2021

A multicenter, community-based, mixed methods assessment of the acceptability of a triple drug regimen for elimination of lymphatic filariasis.

PLoS Negl Trop Dis 2021 Mar 3;15(3):e0009002. Epub 2021 Mar 3.

Washington University, St. Louis, Missouri, United States of America.

Background: Many countries will not reach elimination targets for lymphatic filariasis in 2020 using the two-drug treatment regimen (diethylcarbamazine citrate [DEC] and albendazole [DA]). A cluster-randomized, community-based safety study performed in Fiji, Haiti, India, Indonesia and Papua New Guinea tested the safety and efficacy of a new regimen of ivermectin, DEC and albendazole (IDA).

Methodology/principal Findings: To assess acceptability of IDA and DA, a mixed methods study was embedded within this community-based safety study. The study objective was to assess the acceptability of IDA versus DA. Community surveys were performed in each country with randomly selected participants (>14 years) from the safety study participant list in both DA and IDA arms. In depth interviews (IDI) and focus group discussions (FGD) assessed acceptability-related themes. In 1919 individuals, distribution of sex, microfilariae (Mf) presence and circulating filarial antigenemia (CFA), adverse events (AE) and age were similar across arms. A composite acceptability score summed the values from nine indicators (range 9-36). The median (22.5) score indicated threshold of acceptability. There was no difference in scores for IDA and DA regimens. Mean acceptability scores across both treatment arms were: Fiji 33.7 (95% CI: 33.1-34.3); Papua New Guinea 32.9 (95% CI: 31.9-33.8); Indonesia 30.6 (95% CI: 29.8-31.3); Haiti 28.6 (95% CI: 27.8-29.4); India 26.8 (95% CI: 25.6-28) (P<0.001). AE, Mf or CFA were not associated with acceptability. Qualitative research (27 FGD; 42 IDI) highlighted professionalism and appreciation for AE support. No major concerns were detected about number of tablets. Increased uptake of LF treatment by individuals who had never complied with MDA was observed.

Conclusions/significance: IDA and DA regimens for LF elimination were highly and equally acceptable in individuals participating in the community-based safety study in Fiji, Haiti, India, Indonesia, and Papua New Guinea. Country variation in acceptability was significant. Acceptability of the professionalism of the treatment delivery was highlighted.
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http://dx.doi.org/10.1371/journal.pntd.0009002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928496PMC
March 2021

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.

bioRxiv 2021 Feb 23. Epub 2021 Feb 23.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

Summmary: Complement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.
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http://dx.doi.org/10.1101/2021.02.22.432177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924264PMC
February 2021

Asthma in patients with suspected and diagnosed coronavirus disease 2019.

Ann Allergy Asthma Immunol 2021 Feb 25. Epub 2021 Feb 25.

Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri. Electronic address:

Background: Patients with asthma are comparatively susceptible to respiratory viral infections and more likely to develop severe symptoms than people without asthma. During the coronavirus disease 2019 (COVID-19) pandemic, it is necessary to adequately evaluate the characteristics and outcomes of the population with asthma in the population tested for and diagnosed as having COVID-19.

Objective: To perform a study to assess the impact of asthma on COVID-19 diagnosis, presenting symptoms, disease severity, and cytokine profiles.

Methods: This was an analysis of a prospectively collected cohort of patients suspected of having COVID-19 who presented for COVID-19 testing at a tertiary medical center in Missouri between March 2020 and September 2020. We classified and analyzed patients according to their pre-existing asthma diagnosis and subsequent COVID-19 testing results.

Results: Patients suspected of having COVID-19 (N = 435) were enrolled in this study. The proportions of patients testing positive for COVID-19 were 69.2% and 81.9% in the groups with asthma and without asthma, respectively. The frequencies of relevant symptoms were similar between the groups with asthma with positive and negative COVID-19 test results. In the population diagnosed as having COVID-19 (n = 343), asthma was not associated with several indicators of COVID-19 severity, including hospitalization, admission to an intensive care unit, mechanical ventilation, death due to COVID-19, and in-hospital mortality after multivariate adjustment. Patients with COVID-19 with asthma exhibited significantly lower levels of plasma interleukin-8 than patients without asthma (adjusted P = .02).

Conclusion: The population with asthma is facing a challenge in preliminary COVID-19 evaluation owing to an overlap in the symptoms of COVID-19 and asthma. However, asthma does not increase the risk of COVID-19 severity if infected.
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http://dx.doi.org/10.1016/j.anai.2021.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905379PMC
February 2021

Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: results from SARP-3.

J Allergy Clin Immunol 2021 Feb 9. Epub 2021 Feb 9.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS. Electronic address:

Background: Currently there is limited knowledge of what imaging assessments of asthma are associated with accelerated longitudinal lung function decline.

Objectives: We aimed to assess whether quantitative computerized tomography (qCT) metrics are associated with longitudinal lung function decline and morbidity in asthma.

Methods: We analyzed 205 qCT scans of adult asthma patients, and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future lung function change, future exacerbation rate, and changes in validated measurements of morbidity.

Results: Greater baseline wall area percent (WA%) (β=-0.15, 95% CI -0.26 to -0.05, P<0.01), hyperinflation% (β=-0.25, 95% CI -0.41 to -0.09, P<0.01), and Jacobian gradient measurements (cranial-caudal β=10.64, CI 3.79 to 17.49, P<0.01; posterior-anterior β=-9.14, CI -15.49 to -2.78, P<0.01) were associated with more severe future lung function decline. Additionally, greater WA% (rate ratio=1.06, CI 1.01 to 1.10, P=0.02), air-trapping% (rate ratio=1.01, CI 1.00 to 1.02, P=0.03), and lower Jacobian determinant mean (rate ratio=0.58, CI 0.41 to 0.82, P<0.01) and Jacobian determinant standard deviation (rate ratio=0.52, CI 0.32 to 0.85, P=0.01) were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires.

Conclusions: Baseline qCT measures of more severe airway remodeling, more small airways disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.
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http://dx.doi.org/10.1016/j.jaci.2021.01.029DOI Listing
February 2021

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19.

JCI Insight 2021 02 22;6(4). Epub 2021 Feb 22.

Division of Cardiothoracic Surgery, Department of Surgery.

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.
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http://dx.doi.org/10.1172/jci.insight.143299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934921PMC
February 2021

SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans.

Res Sq 2020 Dec 31. Epub 2020 Dec 31.

Infection or vaccination induces a population of long-lived bone marrow plasma cells (BMPCs) that are a persistent and essential source of protective antibodies1-5. Whether this population is induced in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unknown. Recent reports have suggested that SARS-CoV-2 convalescent patients experience a rapid decay in their antigen-specific serum antibodies, raising concerns that humoral immunity against this virus may be short-lived6-8. Here we show that in patients who experienced mild infections (n=73), serum anti-SARS-CoV-2 spike (S) antibodies indeed decline rapidly in the first 3 to 4 months after infection. However, this is followed by a more stable phase between 4- and 8-months after infection with a slower serum anti-S antibody decay rate. The level of serum antibodies correlated with the frequency of S-specific long-lived BMPCs obtained from 18 SARS-CoV-2 convalescent patients 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy subjects with no history of SARS-CoV-2 infection. Comparable frequencies of BMPCs specific to contemporary influenza virus antigens or tetanus and diphtheria vaccine antigens were present in aspirates in both groups. Circulating memory B cells (MBCs) directed against the S protein were detected in the SARS-CoV-2 convalescent patients but not in uninfected controls, whereas both groups had MBCs against influenza virus hemagglutinin. Overall, we show that robust antigen specific long-lived BMPCs and MBCs are induced after mild SARS-CoV-2 infection of humans.
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http://dx.doi.org/10.21203/rs.3.rs-132821/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781328PMC
December 2020

No cases of asymptomatic SARS-CoV-2 infection among healthcare staff in a city under lockdown restrictions: lessons to inform 'Operation Moonshot'.

J Public Health (Oxf) 2020 Dec 26. Epub 2020 Dec 26.

Department of Respiratory Sciences, University of Leicester, Leicester LE1 7RH, UK.

Background: Leicester was the first city in the UK to have 'local lockdown' measures imposed in response to high community rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. As part of this response, a directive was issued by NHS England to offer testing of asymptomatic healthcare workers (HCWs) at University Hospitals of Leicester NHS Trust (UHL) for SARS-CoV-2 infection.

Methods: Between 20 July and 14 August 2020, we invited all HCWs at UHL to attend for SARS-CoV-2 testing by nucleic acid amplification (NAAT). We combined the result of this assay with demographic information from the electronic staff record.

Results: A total of 1150 staff (~8% of the workforce) volunteered. The median age was 46 years (IQR 34-55), 972 (84.5%) were female; 234 (20.4%) were of South Asian and 58 (5.0%) of Black ethnicity; 564 (49.0%) were nurses/healthcare assistants. We found no cases of asymptomatic infection. In comparison, average community test positivity rate in Leicester city was 2.6%.

Conclusions: Within the context of local lockdowns due to high community transmission rates, voluntary testing of asymptomatic staff has low uptake and low yield and thus its premise and cost-effectiveness should be re-considered.
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http://dx.doi.org/10.1093/pubmed/fdaa237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798961PMC
December 2020

What Mid-term Patient-reported Outcome Measure Scores, Reoperations, and Complications Are Associated with Concurrent Hip Arthroscopy and Periacetabular Osteotomy to Treat Dysplasia with Associated Intraarticular Abnormalities?

Clin Orthop Relat Res 2020 Dec 8. Epub 2020 Dec 8.

A. I. Edelstein, Medical College of Wisconsin, Milwaukee, WI, USA J. J. Nepple, W. Abu-Amer, C. Pascual-Garrido, C. W. Goss, J. C. Clohisy, Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, USA.

Background: Periacetabular osteotomy (PAO) is a well-accepted treatment for acetabular dysplasia, but treatment success is not uniform. Concurrent hip arthroscopy has been proposed for select patients to address intraarticular abnormalities. The patient-reported outcomes, complications, and reoperations for concurrent arthroscopy and PAO to treat acetabular dysplasia remain unclear.

Questions/purposes: (1) What are the functional outcome scores among select patients treated with PAO plus concurrent hip arthroscopy at mid-term follow-up? (2) What factors are associated with conversion to THA or persistent symptoms (modified Harris hip score ≤ 70 or WOMAC pain subscore ≥ 10)? (3) What proportion of patients underwent further hip preservation surgery at mid-term follow-up? (4) What are the complications associated with the procedure?

Methods: Between November 2005 and December 2012, 78 patients (81 hips) who presented with symptomatic acetabular dysplasia-defined as a lateral center-edge angle less than 20° with hip pain for more than 3 months that interfered with daily function-had undergone unsuccessful nonsurgical treatment, had associated intraarticular abnormalities on MRI, and underwent combined hip arthroscopy and PAO. Eleven patients did not have minimum 4-year follow-up and were excluded, leaving 67 patients (70 hips) who met our inclusion criteria and had a mean follow-up duration of 6.5 ± 1.6 years. We retrospectively evaluated patient-reported outcomes at final follow-up using the University of California Los Angeles (UCLA) activity score, the modified Harris Hip Score (mHHS), and the WOMAC pain subscore. Conversion to THA or persistent symptoms were considered clinical endpoints. Repeat surgical procedures were drawn from a prospectively maintained database, and major complications were graded according to the validated Clavien-Dindo classification (Grade III or IV). Student t-tests, chi-square tests, and Fisher exact tests identified the association of patient factors, radiographic measures, and surgical details with clinical endpoints. For patients who underwent bilateral procedures, only the first hip was included in our analyses.

Results: At final follow-up, the mean mHHS for all patients improved from a mean ± SD of 55 ± 19 points to 85 ± 17 points (p < 0.001), the UCLA activity score improved from 6.5 ± 2.7 points to 7.5 ± 2.2 points (p = 0.01), and the WOMAC pain score improved from 9.1 ± 4.3 points to 3.2 ± 3.9 points (p < 0.001). Three percent (2 of 67) of patients underwent subsequent THA, while 21% (15 of 70) of hips were persistently symptomatic, defined as mHHS less than or equal to 70 or WOMAC pain subscore greater than or equal to 10. Univariate analyses indicated that no patient demographics, preoperative or postoperative radiographic metrics, or intraoperative findings or procedures were associated with subsequent THA or symptomatic hips. Worse baseline mHHS and WOMAC pain scores were associated with subsequent THA or symptomatic hips. Seven percent (5 of 67) of patients underwent repeat hip preservation surgery for recurrent symptoms, and 4% (3 of 67) of patients had major complications (Clavien-Dindo Grade III or IV).

Conclusion: This study demonstrated that concurrent hip arthroscopy and PAO to treat symptomatic acetabular dysplasia (with intraarticular abnormalities) has good clinical outcomes at mid-term follow-up in many patients; however, persistent symptoms or conversion to THA affected almost a quarter of the sample. We noted an acceptable complication profile. Further study is needed to directly compare this approach to more traditional techniques that do not involve arthroscopy. We do not use isolated hip arthroscopy to treat symptomatic acetabular dysplasia.

Level Of Evidence: Level IV, therapeutic study.
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http://dx.doi.org/10.1097/CORR.0000000000001599DOI Listing
December 2020

Random forest analysis identifies change in serum creatinine and listing status as the most predictive variables of an outcome for young children on liver transplant waitlist.

Pediatr Transplant 2020 Nov 24:e13932. Epub 2020 Nov 24.

Department of Surgery, Washington University in St. Louis, Barnes Jewish Hospital, St. Louis, MO, USA.

Young children listed for liver transplant have high waitlist mortality (WL), which is not fully predicted by the PELD score. SRTR database was queried for children < 2 years listed for initial LT during 2002-17 (n = 4973). Subjects were divided into three outcome groups: bad (death or removal for too sick to transplant), good (spontaneous improvement), and transplant. Demographic, clinical, listing history, and laboratory variables at the time of listing (baseline variables), and changes in variables between listing and prior to outcome (trajectory variables) were analyzed using random forest (RF) analysis. 81.5% candidates underwent LT, and 12.3% had bad outcome. RF model including both baseline and trajectory variables improved prediction compared to model using baseline variables alone. RF analyses identified change in serum creatinine and listing status as the most predictive variables. 80% of subjects listed with a PELD score at time of listing and outcome underwent LT, while ~70% of subjects in both bad and good outcome groups were listed with either Status 1 (A or B) prior to an outcome, regardless of initial listing status. Increase in creatinine on LT waitlist was predictive of bad outcome. Longer time spent on WL was predictive of good outcome. Subjects with biliary atresia, liver tumors, and metabolic disease had LT rate >85%, while >20% of subjects with acute liver failure had a bad outcome. Change in creatinine, listing status, need for RRT, time spent on LT waitlist, and diagnoses were the most predictive variables.
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http://dx.doi.org/10.1111/petr.13932DOI Listing
November 2020

Demographic and occupational determinants of anti-SARS-CoV-2 IgG seropositivity in hospital staff.

J Public Health (Oxf) 2020 Nov 16. Epub 2020 Nov 16.

Department of Respiratory Sciences, University of Leicester, Leicester LE1 7RH, UK.

Background: Although evidence suggests that demographic characteristics including minority ethnicity increase the risk of infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is unclear whether these characteristics, together with occupational factors, influence anti-SARS-CoV-2 IgG seroprevalence in hospital staff.

Methods: We conducted cross-sectional surveillance examining seroprevalence of anti-SARS-CoV-2 IgG amongst staff at University Hospitals of Leicester (UHL) NHS Trust. We quantified seroprevalence stratified by ethnicity, occupation and seniority of practitioner and used logistic regression to examine demographic and occupational factors associated with seropositivity.

Results: A total of 1148/10662 (10.8%) hospital staff members were seropositive. Compared to White staff (seroprevalence 9.1%), seroprevalence was higher in South Asian (12.3%) and Black (21.2%) staff. The occupations and department with the highest seroprevalence were nurses/healthcare assistants (13.7%) and the Emergency Department (ED)/Acute Medicine (17.5%), respectively. Seroprevalence decreased with seniority in medical/nursing practitioners. Minority ethnicity was associated with seropositivity on an adjusted analysis (South Asian: aOR 1.26; 95%CI: 1.07-1.49 and Black: 2.42; 1.90-3.09). Anaesthetics/ICU staff members were less likely to be seropositive than ED/Acute medicine staff (0.41; 0.27-0.61).

Conclusions: Ethnicity and occupational factors, including specialty and seniority, are associated with seropositivity for anti-SARS-Cov-2 IgG. These findings could be used to inform occupational risk assessments for front-line healthcare workers.
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http://dx.doi.org/10.1093/pubmed/fdaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717317PMC
November 2020

Lung function trajectories and bronchial hyperresponsiveness during childhood following severe RSV bronchiolitis in infancy.

Pediatr Allergy Immunol 2021 Apr 6;32(3):457-464. Epub 2020 Nov 6.

The Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.

Background: Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis.

Methods: In a prospective cohort of 206 children with their first episode of RSV-confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5-16 years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12 years of age, respectively. Longitudinal changes in FEV , FVC, and FEV /FVC z-scores and methacholine PC were analyzed.

Results: 55% of the study cohort (N = 122) were male, and 55% were Caucasian. During follow-up, longitudinal changes in z-scores for pre- and post-bronchodilator FEV (P < .0001) FVC (P < .0001) and FEV /FVC (P < .0001 for pre- and 0.007 for post-bronchodilator) from age 5 to 10-16 years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC geometric mean increased from 0.28 mg/mL at 7 years to 0.53 mg/mL at 12 years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P = .0003).

Conclusions: Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre- and post-bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post-bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood.
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http://dx.doi.org/10.1111/pai.13399DOI Listing
April 2021

Impact of annual and semi-annual mass drug administration for Lymphatic Filariasis and Onchocerciasis on Hookworm Infection in Côte d'Ivoire.

PLoS Negl Trop Dis 2020 09 25;14(9):e0008642. Epub 2020 Sep 25.

Infectious Diseases Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Mass Drug Administration (MDA) programs to eliminate Lymphatic Filariasis (LF) in western Africa use the anthelminthics ivermectin plus albendazole. These drugs have the potential to impact also Soil-Transmitted Helminth (STH) infections, since the drugs have a broad range of anthelminthic activity. Integration of preventive chemotherapy efforts for LF, onchocerciasis and STH is recommended by the World Health Organization (WHO) in order to avoid duplication of MDA and to reduce costs. The objective of the current study was to determine whether five semi-annual rounds of community-wide MDA to eliminate LF and onchocerciasis have a greater impact on STH than three annual rounds of MDA with similar compliance. The effects of MDA using ivermectin (IVM, 0.2 mg/kg) combined with albendazole (ALB, 400 mg) on the prevalence and intensity of hookworm infection were evaluated in the Abengourou (annual MDA) and Akoupé (semi-annual MDA) health Districts in eastern Côte d'Ivoire from 2014 to 2017. A cross-sectional approach was used together with mixed logistic regression, and mixed linear models. Subjects were tested for STH using the Kato-Katz technique before the first round of MDA and 12, 24, and 36 months after the first round of MDA. The mean self-reported MDA compliance assessed during the survey was 65%, and no difference was observed between treatment areas. These results were confirmed by an independent coverage survey as recommended by WHO. Hookworm was the most prevalent STH species in both areas (23.9% vs 12.4%) and the prevalence of other STH species was less than 1%. The crude prevalence of hookworm dropped significantly, from 23.9% to 5.5% (p <0.001, 77% reduction) in the annual MDA treatment area and from 12.4% to 1.9% (p <0.001, 85% reduction) in the semi-annual treatment area. The average intensity of hookworm infection decreased in the annual MDA area (406.2 epg to 118.3 epg), but not in the semi-annual MDA area (804.9 epg to 875.0 epg). Moderate and heavy infections (1% and 1.3% at baseline) were reduced to 0% and 0.4% in the annual and semi-annual treatment areas, respectively. Using a mixed logistic regression model, and after adjusting for baseline prevalence, only the year 2 re-examination showed a difference in prevalence between treatments (OR: 2.26 [95% CI: 1.03, 4.98], p = 0.043). Analysis of intensity of hookworm infection indicated also that treatment differences varied by follow-up visit. In conclusion twelve months after the last treatment cycle, three annual and five semi-annual rounds of community-wide MDA with the combination of IVM and ALB showed strong, but similar impact on hookworm prevalence and intensity in eastern Côte d'Ivoire. Therefore, an annual MDA regimen seems to be an efficient strategy to control hookworm infection in endemic areas with low and moderate infection prevalence. Trial registration: The study was registered at ClinicalTrial.gov under the number NTC02032043.
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http://dx.doi.org/10.1371/journal.pntd.0008642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540880PMC
September 2020

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19.

bioRxiv 2020 Jul 30. Epub 2020 Jul 30.

Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether the appearance of cell-free MT-DNA is linked to poor COVID-19 outcomes remains undetermined. Here, we quantified circulating MT-DNA in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at the time of hospital presentation. Circulating MT-DNA were sharply elevated in patients who eventually died, required ICU admission or intubation. Multivariate regression analysis revealed that high circulating MT-DNA levels is an independent risk factor for all of these outcomes after adjusting for age, sex and comorbidities. Additionally, we found that circulating MT-DNA has a similar or superior area-under-the curve when compared to clinically established measures of systemic inflammation, as well as emerging markers currently of interest as investigational targets for COVID-19 therapy. These results show that high circulating MT-DNA levels is a potential indicator for poor COVID-19 outcomes.
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http://dx.doi.org/10.1101/2020.07.30.227553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402031PMC
July 2020

Exposure to COVID-19 patients increases physician trainee stress and burnout.

PLoS One 2020 6;15(8):e0237301. Epub 2020 Aug 6.

Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, United States of America.

The coronavirus disease 2019 (COVID-19) pandemic has put considerable physical and emotional strain on frontline healthcare workers. Among frontline healthcare workers, physician trainees represent a unique group-functioning simultaneously as both learners and caregivers and experiencing considerable challenges during the pandemic. However, we have a limited understanding regarding the emotional effects and vulnerability experienced by trainees during the pandemic. We investigated the effects of trainee exposure to patients being tested for COVID-19 on their depression, anxiety, stress, burnout and professional fulfillment. All physician trainees at an academic medical center (n = 1375) were invited to participate in an online survey. We compared the measures of depression, anxiety, stress, burnout and professional fulfillment among trainees who were exposed to patients being tested for COVID-19 and those that were not, using univariable and multivariable models. We also evaluated perceived life stressors such as childcare, home schooling, personal finances and work-family balance among both groups. 393 trainees completed the survey (29% response rate). Compared to the non-exposed group, the exposed group had a higher prevalence of stress (29.4% vs. 18.9%), and burnout (46.3% vs. 33.7%). The exposed group also experienced moderate to extremely high perceived stress regarding childcare and had a lower work-family balance. Multivariable models indicated that trainees who were exposed to COVID-19 patients reported significantly higher stress (10.96 [95% CI, 9.65 to 12.46] vs 8.44 [95% CI, 7.3 to 9.76]; P = 0.043) and were more likely to be burned out (1.31 [95% CI, 1.21 to1.41] vs 1.07 [95% CI, 0.96 to 1.19]; P = 0.002]. We also found that female trainees were more likely to be stressed (P = 0.043); while unmarried trainees were more likely to be depressed (P = 0.009), and marginally more likely to have anxiety (P = 0.051). To address these challenges, wellness programs should focus on sustaining current programs, develop new and targeted mental health resources that are widely accessible and devise strategies for creating awareness regarding these resources.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237301PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410237PMC
August 2020

Safety and efficacy of co-administered diethylcarbamazine, albendazole and ivermectin during mass drug administration for lymphatic filariasis in Haiti: Results from a two-armed, open-label, cluster-randomized, community study.

PLoS Negl Trop Dis 2020 06 8;14(6):e0008298. Epub 2020 Jun 8.

Ministère de la Santé et de la Population, Port-au-Prince, Haïti.

In Haiti, 22 communes still require mass drug administration (MDA) to eliminate lymphatic filariasis (LF) as a public health problem. Several clinical trials have shown that a single oral dose of ivermectin (IVM), diethylcarbamazine (DEC) and albendazole (ALB) (IDA) is more effective than DEC plus ALB (DA) for clearing Wuchereria bancrofti microfilariae (Mf). We performed a cluster-randomized community study to compare the safety and efficacy of IDA and DA in an LF-endemic area in northern Haiti. Ten localities were randomized to receive either DA or IDA. Participants were monitored for adverse events (AE), parasite antigenemia, and microfilaremia. Antigen-positive participants were retested one year after MDA to assess treatment efficacy. Fewer participants (11.0%, 321/2917) experienced at least one AE after IDA compared to DA (17.3%, 491/2844, P<0.001). Most AEs were mild, and the three most common AEs reported were headaches, dizziness and abdominal pain. Serious AEs developed in three participants who received DA. Baseline prevalence for filarial antigenemia was 8.0% (239/3004) in IDA localities and 11.5% (344/2994) in DA localities (<0.001). Of those with positive antigenemia, 17.6% (42/239) in IDA localities and 20.9% (72/344, P = 0.25) in DA localities were microfilaremic. One year after treatment, 84% percent of persons with positive filarial antigen tests at baseline could be retested. Clearance rates for filarial antigenemia were 20.5% (41/200) after IDA versus 25.4% (74/289) after DA (P = 0.3). However, 94.4% (34/36) of IDA recipients and 75.9% (44/58) of DA recipients with baseline microfilaremia were Mf negative at the time of retest (P = 0.02). Thus, MDA with IDA was at least as well tolerated and significantly more effective for clearing Mf compared to the standard DA regimen in this study. Effective MDA coverage with IDA could accelerate the elimination of LF as a public health problem in the 22 communes that still require MDA in Haiti.
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http://dx.doi.org/10.1371/journal.pntd.0008298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302858PMC
June 2020

Single-Session Bronchial Thermoplasty Guided by Xe Magnetic Resonance Imaging. A Pilot Randomized Controlled Clinical Trial.

Am J Respir Crit Care Med 2020 08;202(4):524-534

University of Kansas School of Medicine, Kansas City, Kansas.

Adverse events have limited the use of bronchial thermoplasty (BT) in severe asthma. We sought to evaluate the effectiveness and safety of using Xe magnetic resonance imaging (Xe MRI) to prioritize the most involved airways for guided BT. Thirty subjects with severe asthma were imaged with volumetric computed tomography and Xe MRI to quantitate segmental ventilation defects. Subjects were randomized to treatment of the six most involved airways in the first session (guided group) or a standard three-session BT (unguided). The primary outcome was the change in Asthma Quality of Life Questionnaire score from baseline to 12 weeks after the first BT for the guided group compared with after three treatments for the unguided group. There was no significant difference in quality of life after one guided compared with three unguided BTs (change in Asthma Quality of Life Questionnaire guided = 0.91 [95% confidence interval, 0.28-1.53]; unguided = 1.49 [95% confidence interval, 0.84-2.14];  = 0.201). After one BT, the guided group had a greater reduction in the percentage of poorly and nonventilated lung from baseline when compared with unguided (-17.2%;  = 0.009). Thirty-three percent experienced asthma exacerbations after one guided BT compared with 73% after three unguided BTs ( = 0.028). Results of this pilot study suggest that similar short-term improvements can be achieved with one BT treatment guided by Xe MRI when compared with standard three-treatment-session BT with fewer periprocedure adverse events.
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http://dx.doi.org/10.1164/rccm.201905-1021OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427382PMC
August 2020

The TDR MOOC training in implementation research: evaluation of feasibility and lessons learned in Rwanda.

Pilot Feasibility Stud 2020 15;6:66. Epub 2020 May 15.

2Regional Alliance for Sustainable Development (RASD) Rwanda, Kigali, Rwanda.

Background: Hypertension (HTN) affects nearly 1 billion people globally and is a major cause of morbidity and mortality. In low- and middle-income countries (LMICs), HTN represents an unmet health care gap that can be addressed by strengthening national health care systems. The National Heart, Lung, and Blood Institute recently funded the T4 Translation Research Capacity Building Initiative in Low Income Countries (TREIN) program to build capacity in dissemination and implementation (D&I) research in HTN in LMICs. The Special Programme for Research and Training in Tropical Diseases (TDR) at the World Health Organization (WHO) recently developed a massive open online course (MOOC) to train in D&I. Herein, we report on the use of the TDR WHO MOOC in D&I for the TREIN program in Rwanda, assessing feasibility of the MOOC and D&I competencies after MOOC training.

Methods: Participants in one-group MOOC training completed pre- and post-training questionnaires to assess dissemination and implementation (D&I) competency outcomes and feasibility. D&I competencies were measured by use of a scale developed for a US-based training program, with the change in competency scores assessed by paired test. Feasibility was measured by completion of homework and final project assignment and analyzed using descriptive statistics.

Results: Of the 92 trainees enrolled, 35 (38%) completed all MOOC components. D&I competency scores showed strong evidence of improvements from pre- to post-test. The full-scale average score improved by an average of 1.09 points, representing an effect size of 1.25 (CI 0.48-2.00); all four subscales also showed strong evidence of improvements. Trainees reported challenges to MOOC course completion that included technological issues (i.e., limited internet access) and competing demands (i.e., work, family).

Conclusions: In the context of LMIC training, the MOOC course was feasible and course completion showed improvement in D&I competency scores. While the program was designed with a focus on training for tropical diseases, there is potential for scalability to a wider audience of health care researchers, workers, administrators, and policymakers in LMIC interested in D&I research in non-communicable diseases.
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http://dx.doi.org/10.1186/s40814-020-00607-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229620PMC
May 2020

Dissemination and Implementation Program in Hypertension in Rwanda: Report on Initial Training and Evaluation.

Glob Heart 2019 06;14(2):135-141

Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and in low- and middle-income countries, and hypertension (HTN) is a major risk factor for CVD. Although effective evidence-based interventions for control of HTN in high-income countries exist, implementation of these in low- and middle-income countries has been challenging due to limited capacity and infrastructure for late-phase translational research. In Rwanda, the 2015 STEPS NCD (STEPwise Approach to Surveillance of Noncommunicable Diseases) risk survey reported an overall prevalence of HTN of 15% (95% confidence interval [CI]: 13.8 to 16.3) for those ages 15 to 64 years; prevalence increased with increasing age to 39% (95% CI: 35.7 to 43.1) for those ages 55 to 64 years; CVD was the third most common cause of mortality (7%). Suboptimal infrastructure and capacity in Rwanda hinders research and community knowledge for HTN control.

Objectives: To address the issue of suboptimal capacity to implement evidence-based interventions in HTN, this project was designed with the following objectives: 1) to develop a regional needs assessment of infrastructure for dissemination and implementation (D & I) strategies for HTN-CVD control; 2) to develop HTN-CVD research capacity through creation of countrywide resources such as core research facilities and training in the fields of HTN-CVD, D & I, and biostatistics; and 3) to engage and train multiple stakeholders in D & I and HTN-CVD evidence-based interventions.

Methods: A weeklong training program in HTN-CVD, biostatistics, and D & I was conducted in Rwanda in August 2018, and pre- and post-D & I training competency questionnaires were administered.

Results: Questionnaire results show a statistically significant increase in D & I knowledge and skills as a result of training (full scale pre- to post-test scores: 2.12 ± 0.78 vs. 3.94 ± 0.42; p < 0.0001).

Conclusions: Using principles of community engagement and train-the-trainer methods, we will continue to adapt guidelines and treatments for HTN-CVD developed in high-income countries to the context of Rwanda with the goal of establishing a sustainable platform to address the burden of disease from HTN-CVD.
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http://dx.doi.org/10.1016/j.gheart.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816501PMC
June 2019

Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach.

PLoS Negl Trop Dis 2019 07 17;13(7):e0007541. Epub 2019 Jul 17.

Washington University, St. Louis, Missouri, United States of America.

Background: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios.

Methodology/principal Findings: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing.

Conclusions/significance: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.
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http://dx.doi.org/10.1371/journal.pntd.0007541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663033PMC
July 2019

The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study.

PLoS Med 2019 06 24;16(6):e1002839. Epub 2019 Jun 24.

ICMR-Vector Control Research Centre, Puducherry, India.

Background: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings.

Methods And Findings: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites.

Conclusions: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA.

Trial Registration: Clinicaltrials.gov registration number: NCT02899936.
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http://dx.doi.org/10.1371/journal.pmed.1002839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590784PMC
June 2019

Mapping of lymphatic filariasis in loiasis areas: A new strategy shows no evidence for Wuchereria bancrofti endemicity in Cameroon.

PLoS Negl Trop Dis 2019 03 8;13(3):e0007192. Epub 2019 Mar 8.

Infectious Diseases Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Background: Mapping of lymphatic filariasis (LF) caused by Wuchereria bancrofti largely relies on the detection of circulating antigen using ICT cards. Several studies have recently shown that this test can be cross-reactive with sera of subjects heavily infected with Loa loa and thus mapping results in loiasis endemic areas may be inaccurate.

Methodology/principal Findings: In order to develop an LF mapping strategy for areas with high loiasis prevalence, we collected day blood samples from 5,001 subjects residing in 50 villages that make up 6 health districts throughout Cameroon. Antigen testing using Filarial Test Strip (FTS, a novel platform that uses the same reagents as ICT) revealed an overall positivity rate of 1.1% and L. loa microfilaria (Mf) rates of up to 46%. Among the subjects with 0 to 8,000 Mf/ml in day blood, only 0.4% were FTS positive, while 22.2% of subjects with >8,000 Mf/ml were FTS positive. A Mf density of >8,200 Mf/ml was determined as the cut point at which positive FTS results should be excluded from the analysis. No FTS positive samples were also positive for W. bancrofti antibodies as measured by two different point of care tests that use the Wb123 antigen not found in L. loa. Night blood examination of the FTS positive subjects showed a high prevalence of L. loa Mf with densities up to 12,710 Mf/ml. No W. bancrofti Mf were identified, as confirmed by qPCR. Our results show that high loads of L. loa Mf in day blood are a reliable indicator of FTS positivity, and Wb123 rapid test proved to be relatively specific.

Conclusions/significance: Our study provides a simple day blood-based algorithm for LF mapping in loiasis areas. The results indicate that many districts that were formerly classified as endemic for LF in Cameroon are non-endemic and do not require mass drug administration for elimination of LF.
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http://dx.doi.org/10.1371/journal.pntd.0007192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436748PMC
March 2019

Metagenomic analysis of DNA viruses from posttransplant lymphoproliferative disorders.

Cancer Med 2019 03 29;8(3):1013-1023. Epub 2019 Jan 29.

Division of Pediatric Infectious Diseases, Washington University School of Medicine, St Louis, MO, USA.

Posttransplant lymphoproliferative disorders (PTLDs), 50%-80% of which are strongly associated with Epstein-Barr virus (EBV), carry a high morbidity and mortality. Most clinical/epidemiological/tumor characteristics do not consistently associate with worse patient survival, so our aim was to identify if other viral genomic characteristics associated better with survival. We extracted DNA from stored paraffin-embedded PTLD tissues at our center, identified viral sequences by metagenomic shotgun sequencing (MSS), and analyzed the data in relation to clinical outcomes. Our study population comprised 69 PTLD tissue samples collected between 1991 and 2015 from 60 subjects. Nucleotide sequences from at least one virus were detected by MSS in 86% (59/69) of the tissues (EBV in 61%, anelloviruses 52%, gammapapillomaviruses 14%, CMV 7%, and HSV in 3%). No viruses were present in higher proportion in EBV-negative PTLD (compared to EBV-positive PTLD). In univariable analysis, death within 5 years of PTLD diagnosis was associated with anellovirus (P = 0.037) and gammapapillomavirus (P = 0.036) detection by MSS, higher tissue qPCR levels of the predominant human anellovirus species torque teno virus (TTV; P = 0.016), T cell type PTLD, liver, brain or bone marrow location. In multivariable analyses, T cell PTLD (P = 0.006) and TTV PCR level (P = 0.012) remained significant. In EBV-positive PTLD, EBNA-LP, EBNA1 and EBNA3C had significantly higher levels of nonsynonymous gene variants compared to the other EBV genes. Multiple viruses are detectable in PTLD tissues by MSS. Anellovirus positivity, not EBV positivity,was associated with worse patient survival in our series. Confirmation and extension of this work in larger multicenter studies is desirable.
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http://dx.doi.org/10.1002/cam4.1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434222PMC
March 2019

Using only a subset of pneumococcal serotypes is reliable for the diagnosis of specific antibody deficiency in children: A proof-of-concept study.

Pediatr Allergy Immunol 2019 05 11;30(3):392-395. Epub 2019 Feb 11.

Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri.

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http://dx.doi.org/10.1111/pai.13026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488433PMC
May 2019

Comparison of the Impact of Annual and Semiannual Mass Drug Administration on Lymphatic Filariasis Prevalence in Flores Island, Indonesia.

Am J Trop Med Hyg 2019 02;100(2):336-343

Infectious Diseases Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

We compared the impact of annual and semiannual mass drug administration (MDA) on the prevalence of and in Flores Island. Two villages (Paga, only; Lewomada, co-endemic) received annual MDA with diethylcarbamazine/albendazole and a larger village (Pruda, co-endemic) received semiannual MDA. Infection parameters (microfilariae [Mf], antibodies to recombinant filarial antigen BmR1 [Brugia Rapid (BR)], and a test for antigenemia [immunochromatographic test (ICT)]) were assessed before and after treatment. The crude Mf prevalence in Pruda decreased after five semiannual treatments from 14.2% to 1.2%, whereas the Mf prevalence in the other two villages decreased after three annual treatments from 3.9% to 0% and from 5% to 0.3%, respectively. ICT positivity prevalence in Pruda and Lewomada decreased from 22.9% and 6.5% to 7% and 0.8%, respectively, whereas BR antibody prevalence in Pruda, Lewomada, and Paga decreased from 28.9%, 31.7%, and 12.5% to 3.6%, 4.1%, and 1.8%, respectively. Logistic regression analysis indicated that that Mf, BR, and ICT prevalence decreased significantly over time and that for the Mf and ICT outcomes the semiannual treatment had higher odds of positivity. Model-adjusted prevalence estimates revealed that apparent differences in treatment effectiveness were driven by differences in baseline prevalence and that adjusted prevalence declined more rapidly in the semiannual treatment group. We conclude that in this setting, annual MDA was sufficient to reduce Mf prevalence to less than 1% in areas with low to moderate baseline prevalence. Semiannual MDA was useful for rapidly reducing Mf prevalence in an area with higher baseline endemicity.
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http://dx.doi.org/10.4269/ajtmh.18-0570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367633PMC
February 2019

Using the newer Kidney Disease: Improving Global Outcomes criteria, beta-2-microglobulin levels associate with severity of acute kidney injury.

Clin Kidney J 2018 Dec 19;11(6):797-802. Epub 2018 Jul 19.

Division of Pediatric Nephrology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.

Beta-2-microglobulin (B2M) is a marker of proximal tubular injury and glomerular filtration. Analyses using older/non-standardized definitions have shown low efficacy of B2M to predict acute kidney injury (AKI). We assessed if elevated levels of B2M would associate with either the diagnosis of AKI [under current Kidney Disease: Improving Global Outcomes (KDIGO) criteria] or recovery from AKI. We performed a retrospective study, including children who had urine B2M (uB2M) and/or serum B2M (sB2M) measured by immunoturbidimetry in our clinical laboratory between January 2011 and December 2015. We defined AKI based on KDIGO criteria [increase of serum creatinine (sCr) 0.3 mg/dL over 48 h or >50% baseline over 7 days] or urine output <0.5 mL/kg/h for 24 h. Recovery from AKI was defined as a return to baseline sCr within 6 months. We calculated receiver operating characteristics (ROC) area under the curve (AUC). Of 529 patients, 245 developed AKI. Serum and uB2M associated with AKI development (AUCs 0.84 and 0.73, respectively). Patients had a graded higher median sB2M and uB2M with each higher AKI stage. sB2M differentiated Stage I from Stage III AKI (P < 0.001) and Stage II from Stage III AKI (P = 0.004). However, neither uB2M nor sB2M levels associated with recovery from AKI. Only older age {hazard ratio [HR] 0.97, [95% confidence interval (CI) 0.94-0.99]} and need for dialysis [HR 0.39 (95% CI 0.23-0.61)] predicted incomplete recovery after AKI. Using KDIGO criteria, sB2M and uB2M associate with the severity of AKI. Given its relative ease and lower cost, we suggest more widespread use of B2M for AKI detection.
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http://dx.doi.org/10.1093/ckj/sfy056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275448PMC
December 2018

Are Complications After the Bernese Periacetabular Osteotomy Associated With Subsequent Outcomes Scores?

Clin Orthop Relat Res 2019 05;477(5):1157-1163

J. Wells, Department of Orthopaedic Surgery, University of Texas Southwestern Medical School, Dallas, TX, USA P. Schoenecker, J. C. Clohisy, Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, MO, USA J. Petrie, Orlando Health Department of Orthopaedic Surgery, Orlando, FL, USA K. Thomason, A.T. Still University Kirksville College of Osteopathic Medicine, Kirksville, MO, USA C. W. Goss, Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.

Background: The Bernese periacetabular osteotomy (PAO) continues to be a commonly performed nonarthroplasty option to treat acetabular dysplasia, but only a few short-term studies have evaluated complications rigorously after PAO.

Questions/purposes: (1) What complications are observed at 10-year mean followup of the Bernese PAO in patients with symptomatic acetabular dysplasia? (2) What factors are associated with these complications? (3) Do these complications affect clinical outcome scores?

Methods: We reviewed 238 hips in 206 patients treated with PAO from July 1994 to August 2008. Only PAOs performed for symptomatic acetabular dysplasia and those that had at a minimum 4-year followup were included. Patients who went on to THA before 4 years were included in the study. Patients with hip pain who presented with a clinical presentation of symptomatic acetabular dysplasia, radiographic evidence of femoral head uncovering, and a lateral center-edge angle < 25° were considered for PAO and no other juxtaacetabular osteotomy was offered other than PAO. Sixty-two hips had diagnoses other than acetabular dysplasia and 22 were lost to followup. The remaining 154 hips (129 patients) were evaluated by chart review at a mean of 10 years (range, 1.7-20.5 years) using the UCLA Activity Score, modified Harris hip score (mHHS), WOMAC, and radiographic analysis. The mean age at PAO was 26 years (range, 10-60 years) and consisted of 113 female patients (132 hips [86%]) and 16 male patients (22 hips [14%]). Complications were graded using the validated Clavien-Dindo system. Complications were assessed for each hip and the highest complication grade was assigned to the hip if multiple complications occurred. We divided complication grades into three groups for analysis: no complications, Grade 1 complications, and complications that deviated from the standard postoperative course (Grades 2, 3, and 4). There were no Grade 5 complications. Variables with significant (p < 0.05) univariable associations with complications were considered for inclusion in a multivariable model. Outcome variables (mHHS and WOMAC) at the most recent followup visit were analyzed using a generalized estimating equation approach. Analysis of variance was used to compare UCLA at the most recent followup among the complication classes.

Results: Major complications defined as Clavien-Dindo Grade 3/4 occurred in 14 hips (9%). After controlling for potential confounding variables, we found that increasing body mass index (BMI) (odds ratio [OR], 1.16; 95% confidence interval, 1.05-1.25; p = 0.004) was associated with increased risk of complication. In contrast, greater surgeon experience was associated with a decreased risk (OR, 0.3; p = 0.002). Complications were associated with postoperative pain and activity, WOMAC (mean ± SD: 0 complications = 1.5 ± 15.1, 1 complication = 4.3 ± 4.1, 2-3 complications = 3.8 ± 4.6; p = 0.020) and UCLA scores (mean ± SD: 0 complications = 7.8 ± 2, 1 complication = 6.7 ± 2.1, 2-3 complications = 6.5 ± 2; p = 0.003).

Conclusions: Most hips undergoing PAO have few complications. The most common major surgical complication is nonunion. Increasing BMI was a predictor of having a complication, and surgeon experience decreased complication risk. Having a complication adversely affected long-term pain and activity. To minimize complications and maximize outcomes, a patient's BMI should be assessed preoperatively and those with excessive BMI should be counseled on the increased risk of complications. In an experienced surgeon's hands, PAO has few complications at mean 10-year followup and a low risk of permanent disability.

Level Of Evidence: Level III, therapeutic study.
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http://dx.doi.org/10.1097/CORR.0000000000000566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494323PMC
May 2019

A Trial of a Triple-Drug Treatment for Lymphatic Filariasis.

N Engl J Med 2018 11;379(19):1801-1810

From the Center for Global Health and Diseases, Case Western Reserve University School of Medicine (C.L.K., Y.-C.C., B.M., J.W.K.), and the Veterans Affairs Medical Center (C.L.K.), Cleveland; Papua New Guinea Institute of Medical Research, Goroka (J.S., N.S., S.S., L.J.R., P.M.S.); and the Division of Biostatistics (C.W.G.) and Department of Medicine, Infectious Diseases Division (G.J.W.), Washington University School of Medicine, St. Louis.

Background: The World Health Organization has targeted lymphatic filariasis for global elimination by 2020 with a strategy of mass drug administration. This trial tested whether a single dose of a three-drug regimen of ivermectin plus diethylcarbamazine plus albendazole results in a greater sustained clearance of microfilariae than a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and is noninferior to the two-drug regimen administered once a year for 3 years.

Methods: In a randomized, controlled trial involving adults from Papua New Guinea with Wuchereria bancrofti microfilaremia, we assigned 182 participants to receive a single dose of the three-drug regimen (60 participants), a single dose of the two-drug regimen (61 participants), or the two-drug regimen once a year for 3 years (61 participants). Clearance of microfilariae from the blood was measured at 12, 24, and 36 months after trial initiation.

Results: The three-drug regimen cleared microfilaremia in 55 of 57 participants (96%) at 12 months, in 52 of 54 participants (96%) at 24 months, and in 55 of 57 participants (96%) at 36 months. A single dose of the two-drug regimen cleared microfilaremia in 18 of 56 participants (32%) at 12 months, in 31 of 55 participants (56%) at 24 months, and in 43 of 52 participants (83%) at 36 months (P=0.02 for the three-drug regimen vs. a single dose of the two-drug regimen at 36 months). The two-drug regimen administered once a year for 3 years cleared microfilaremia in 20 of 59 participants (34%) at 12 months, in 42 of 56 participants (75%) at 24 months, and in 51 of 52 participants (98%) at 36 months (P=0.004 for noninferiority of the three-drug regimen vs. the two-drug regimen administered once a year for 3 years at 36 months). Moderate adverse events were more common in the group that received the three-drug regimen than in the combined two-drug-regimen groups (27% vs. 5%, P<0.001). There were no serious adverse events.

Conclusions: The three-drug regimen induced clearance of microfilariae from the blood for 3 years in almost all participants who received the treatment and was superior to the two-drug regimen administered once and noninferior to the two-drug regimen administered once a year for 3 years. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01975441 .).
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http://dx.doi.org/10.1056/NEJMoa1706854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194477PMC
November 2018