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Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4

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 3 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 3 annual doses of IA (N = 52), 6 semiannual doses of ALB 400 mg (N = 45), or 6 semiannual doses of ALB 800 mg (N = 47). The primary outcome is amicrofilaremia at 36 months. Results IA was more effective for completely clearing Mf than ALB 400mg or ALB 800mg (79%, 95% confidence interval [CI]: 67–91; vs 48%, 95% CI: 32–66 and 57%, 95% CI: 41–73, respectively). Mean percentage reductions in Mf counts at 36 months relative to baseline tended to be greater after IA (98%, 95% CI: 88–100) than after ALB 400 mg (88%, 95% CI: 78–98) and ALB 800 mg (89%, 95% CI: 79–99) (P = .07 and P = .06, respectively). Adult worm nest numbers (assessed by ultrasound) were reduced in all treatment groups. Treatments were well tolerated. Conclusions 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 where ivermectin cannot be used. Clinical Trials Registration NCT02974049

We compared the impact of three rounds of annual and five rounds of semiannual mass drug administration (MDA) with albendazole plus ivermectin on helminthic infections in Liberia. Repeated annual cross-sectional community surveys were conducted between 2013 and 2019 in individuals of 5 years and older. Primary outcome was the change of infection prevalence estimates from baseline to month 36 (12 months after the last treatment). After three rounds of annual MDA, Wuchereria bancrofti circulating filarial antigen (CFA) and microfilaria (Mf) prevalence estimates decreased from 19.7% to 4.3% and from 8.6% to 0%, respectively; after semiannual MDA, CFA and Mf prevalences decreased from 37.8% to 16.8% and 17.9% to 1%, respectively. Mixed effects logistic regression models indicated that the odds of having Mf decreased by 97% (P < 0.001) at month 36 (similar odds for annual and semiannual MDA zones). A parallel analysis showed that the odds of CFA were reduced by 83% and 69% at 36 months in the annual and semiannual treatment zones, respectively (P < 0.001). Onchocerca volvulus Mf prevalence decreased slightly after multiple MDA rounds in both treatment zones. Reductions in hookworm and Trichuris trichiura prevalences and intensities were slightly greater in the annual treatment zone. Ascaris lumbricoides prevalence rates were relatively unchanged, although infection intensities decreased sharply throughout. Results show that annual and semiannual MDA were equally effective for reducing LF and soil-transmitted helminth infection parameters over a 3-year period, and reductions recorded at month 36 were sustained by routine annual MDA through month 72.

Background Risk factors for nontuberculous mycobacteria (NTM) infections after solid organ transplant (SOT) are not well characterized. Here we aimed to describe these factors. Methods Retrospective, multinational, 1:2 matched case-control study that included SOT recipients ≥12 years old diagnosed with NTM infection from 1 January 2008 to 31 December 2018. Controls were matched on transplanted organ, NTM treatment center, and post-transplant survival greater than or equal to the time to NTM diagnosis. Logistic regression on matched pairs was used to assess associations between risk factors and NTM infections. Results Analyses included 85 cases and 169 controls (59% male, 88% White, median age at time of SOT of 54 years [interquartile range {IQR} 40–62]). NTM infection occurred in kidney (42%), lung (35%), heart and liver (11% each), and pancreas transplant recipients (1%). Median time from transplant to infection was 21.6 months (IQR 5.3–55.2). Most underlying comorbidities were evenly distributed between groups; however, cases were older at the time of NTM diagnosis, more frequently on systemic corticosteroids and had a lower lymphocyte count (all P < .05). In the multivariable model, older age at transplant (adjusted odds ratio [aOR] 1.04; 95 confidence interval [CI], 1.01–1.07), hospital admission within 90 days (aOR, 3.14; 95% CI, 1.41–6.98), receipt of antifungals (aOR, 5.35; 95% CI, 1.7–16.91), and lymphocyte-specific antibodies (aOR, 7.73; 95% CI, 1.07–56.14), were associated with NTM infection. Conclusions Risk of NTM infection in SOT recipients was associated with older age at SOT, prior hospital admission, receipt of antifungals or lymphocyte-specific antibodies. NTM infection should be considered in SOT patients with these risk factors.

Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function.We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma.We analyzed 205 qCT scans of adult patients with asthma 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 change in lung function, future exacerbation rate, and changes in validated measurements of morbidity.Greater baseline wall area percent (β = -0.15 [95% CI = -0.26 to -0.05]; P .01), hyperinflation percent (β = -0.25 [95% CI = -0.41 to -0.09]; P.01), and Jacobian gradient measurements (cranial-caudal β = 10.64 [95% CI = 3.79-17.49]; P .01; posterior-anterior β = -9.14, [95% CI = -15.49 to -2.78]; P .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P = .02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P = .03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P .01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85]; P = .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.Baseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.

Antibody tests can be tools for detecting current or past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 [coronavirus disease 2019 (COVID-19)]) infections. Independent test evaluations are needed to document the performance with different sample sets. We evaluated six lateral flow assays (LFAs) and two laboratory-based tests (EUROIMMUN-SARS-CoV-2 ELISA and Abbott-Architect-SARS-CoV-2-IgG). We tested 210 plasma samples from 89 patients diagnosed with acute COVID-19. These samples were collected at different time points after the onset of symptoms. In addition, 80 convalescent plasma samples, and 168 pre-pandemic samples collected from adults in the United States and in Africa were tested. LFA performance varied widely, and some tests with high sensitivity had low specificity. LFA sensitivities were low (18.8–40.6%) for samples collected 0 to 3 days after symptom onset, and were greater (80.3–96.4%) for samples collected > 14 days after symptom onset. These results are similar to those obtained by ELISA (15.6% and 89.1%) and chemiluminescent microparticle assay (21.4% and 93.1%). The range of test specificity was between 82.7% and 97%. The combined use of two LFAs can increase specificity to more than 99% without a major loss of sensitivity. Because of suboptimal sensitivity with early COVID-19 samples and background reactivity with some pre-pandemic samples, none of the evaluated tests alone is reliable enough for definitive diagnosis of COVID-19 infection. However, antibody testing may be useful for assessing the status of the epidemic or vaccination campaign. Some of the LFAs had sensitivities and specificities that were comparable to those of more expensive laboratory tests, and these may be useful for seroprevalence surveys in resource-limited settings.

Background 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 severe acute respiratory syndrome coronavirus 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 multiple serological assays. Methods We compared the Ortho, Abbott, Roche, an anti‐spike (S) ELISA, and a virus neutralization assay. Relationships relative to FDA‐approved cutoffs under the CCP emergency use authorization were identified in convalescent plasma from a cohort of 79 donors from April 2020. Results Relative to the neutralization assay, the spearman r value of the Ortho Clinical, Abbott, Roche, anti‐S ELISA assays was 0.65, 0.59, 0.45, and 0.76, respectively. The best correlative index for establishing high‐titer units was 3.87 signal‐to‐cutoff (S/C) for the Abbott, 13.82 cutoff index for the Roche, 1:1412 for the anti‐S ELISA, 1:219 by the neutralization assay, and 15.9 S/C by the Ortho Clinical assay. The overall agreement using derived cutoffs compared to a neutralizing titer of 1:250 was 78.5% for Abbott, 74.7% for Roche, 83.5% for the anti‐S ELISA, and 78.5% for Ortho Clinical. DISCUSSION Assays based on antibodies against the nucleoprotein were positively associated with neutralizing titers and 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.

Applying an intersectional framework, we examined sex and racial inequality in COVID-19-related employment loss (ie, job furlough, layoff, and reduced pay) and food insecurity (ie, quality and quantity of food eaten, food worry, and receipt of free meals or groceries) among residents in Saint Louis County, Missouri.We used cross-sectional data from adults aged 18 or older (N = 2,146), surveyed by using landlines or cellular phones between August 12, 2020, and October 27, 2020. We calculated survey-weighted prevalence of employment loss and food insecurity for each group (Black female, Black male, White female, White male). Odds ratios for each group were estimated by using survey-weighted binary and multinomial logistic regression models.Black female residents had higher odds of being laid off, as compared with White male residents (OR = 2.61, 95% CI, 1.24-5.46). Both Black female residents (OR = 4.13, 95% CI, 2.29-7.45) and Black male residents (OR = 2.41, 95% CI, 1.15-5.07) were more likely to receive free groceries, compared with White male residents. Black female (OR = 4.25, 95% CI, 2.28-7.94) and White female residents (OR = 1.93, 95% CI, 1.04-3.60) had higher odds of sometimes worrying about food compared with White male residents. Black women also had higher odds of always or nearly always worrying about food, compared with White men (OR = 2.99, 95% CI, 1.52-5.87).Black women faced the highest odds of employment loss and food insecurity, highlighting the disproportionate impact of COVID-19 among people with intersectional disadvantages of being both Black and female. Interventions to reduce employment loss and food insecurity can help reduce the disproportionately negative social effects among Black women.

Oral and upper respiratory microbiota play important roles in modulating host immune responses to viral infection. As emerging evidence suggests the host microbiome may be involved in the pathophysiology of COVID-19, we aimed to investigate associations between the oral and nasopharyngeal microbiome and COVID-19 severity. We collected saliva (n = 78) and nasopharyngeal swab (n = 66) samples from a COVID-19 cohort and characterized the microbiomes using 16S ribosomal RNA gene sequencing. We also examined associations between the salivary and nasopharyngeal microbiome and age, COVID-19 symptoms, and blood cytokines. SARS-CoV-2 infection status, but not COVID-19 severity, was associated with community-level differences in the oral and nasopharyngeal microbiomes. Salivary and nasopharyngeal microbiome alpha diversity negatively correlated with age and were associated with fever and diarrhea. Several bacterial genera were differentially abundant by COVID-19 severity, including oral Bifidobacterium, Lactobacillus, and Solobacterium, all of which were depleted in patients with severe COVID-19. Nasopharyngeal Paracoccus was depleted while nasopharyngeal Proteus, Cupravidus, and Lactobacillus were increased in patients with severe COVID-19. Further analysis revealed that the abundance of oral Bifidobacterium was negatively associated with plasma concentrations of known COVID-19 biomarkers interleukin 17F (IL-17F) and monocyte chemoattractant protein-1 (MCP-1). In conclusion, our results suggest COVID-19 disease severity is associated with the relative abundance of certain bacterial taxa.

Donor-derived cellfree DNA (cfDNA) is a less-invasive marker of allograft injury compared with kidney biopsy. However, donor-derived cfDNA has not yet been extensively tested in children, where the test may have different characteristics.We assayed donor-derived cfDNA (AlloSure; CareDx) from 290 stored plasma samples from a prospective biobank at our center, collected from 57 children monthly in the first year postkidney transplant between January 2013 and December 2019. We assessed the kinetic changes in donor-derived cfDNA levels within the first year post-transplant. We analyzed donor-derived cfDNA levels for associations with biopsy-proven acute rejection using area under the receiver operating characteristic curve to longitudinal plasma and urine BK viral loads using linear mixed models. We analyzed the prognostic effect of an elevated donor-derived cfDNA level on the eGFR 30 days after the assayThe donor-derived cfDNA levels in children remained persistently elevated for at least 4 months post-transplant, more so if there is greater disparity in size between the donor and the recipient, before reaching a steady low level. A donor-derived cfDNA level of1% discriminated between biopsy-proven acute rejection with a receiver operating characteristic area under the curve of 0.82 (95% confidence interval, 0.71 to 0.93). During BK viruria or viremia, patients had a significantly higher median donor-derived cfDNA than before or after and a significant rise within the same patient. A donor-derived cfDNA of0.5% predicted a wider spread in the eGFR over the next 30 days but not the 12-month outcomes.In children, donor-derived cfDNA is a valuable, less invasive biomarker for assessment of allograft rejection and injury.This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_10_27_CJN03840322.mp3.

Background Onchocerciasis (“river blindness”) has been targeted for elimination. New treatments that kill or permanently sterilize female worms could accelerate this process. Prior studies have shown that triple drug treatment with ivermectin plus diethylcarbamazine and albendazole (IDA) leads to prolonged clearance of microfilaremia in persons with lymphatic filariasis. We now report results from a randomized clinical trial that compared the tolerability and efficacy of IDA vs. a comparator treatment (ivermectin plus albendazole, IA) in persons with onchocerciasis. Methods and findings The study was performed in the Volta region of Ghana. Persons with microfiladermia and palpable subcutaneous nodules were pre-treated with two oral doses of ivermectin (150 μg/kg) separated by at least 6 months prior to treatment with either a single oral dose of ivermectin 150 μg/kg plus albendazole 400 mg (IA), a single oral dose of IDA (IDA1, IA plus diethylcarbamazine (DEC. 6 mg/kg) or three consecutive daily doses of IDA (IDA3). These treatments were tolerated equally well. While adverse events were common (approximately 30% overall), no severe or serious treatment-emergent adverse events were observed. Skin microfilariae were absent or present with very low densities after all three treatments through 18 months, at which time nodules were excised for histological assessment. Nodule histology was evaluated by two independent assessors who were masked regarding participant infection status or treatment assignment. Significantly lower percentages of female worms were alive and fertile in nodules recovered from study participants after IDA1 (40/261, 15.3%) and IDA3 (34/281, 12.1%) than after IA (41/180, 22.8%). This corresponds to a 40% reduction in the percentage of female worms that were alive and fertile after IDA treatments relative to results observed after the IA comparator treatment (P = 0.004). Percentages of female worms that were alive (a secondary outcome of the study) were also lower after IDA treatments (301/574, 52.4%) than after IA (127/198, 64.1%) (P = 0.004). Importantly, some comparisons (including the reduced % of fertile female worms after IDA1 vs IA treatment, which was the primary endpoint for the study) were not statistically significant when results were adjusted for intraclass correlation of worm fertility and viability for worms recovered from individual study participants. Conclusions Results from this pilot study suggest that IDA was well tolerated after ivermectin pretreatment. They also suggest that IDA was more effective than the comparator treatment IA for killing or sterilizing female O. volvulus worms. No other short-course oral treatment for onchocerciasis has been demonstrated to have macrofilaricidal activity. However, this first study was too small to provide conclusive results. Therefore, additional studies will be needed to confirm these promising findings. Trial registration The study is registered at Cinicaltrials.gov under the number NCT04188301.

The coronavirus disease of 2019 (COVID-19) pandemic declared by the World Health Organization on March 11, 2020 impacted healthcare services with provider and patient cancellations, delays, and patient avoidance or delay of emergency department or urgent care. Limited data exist on the population proportion affected by delayed healthcare, which is important for future healthcare planning efforts. Our objective was to evaluate the impact of the COVID-19 pandemic on healthcare service cancellations or delays and delays/avoidance of emergency/urgent care overall and by population characteristics.This was a cross-sectional study.Our sample (n = 2314) was assembled through a phone survey from 8/12/2020-10/27/2020 among non-institutionalized St. Louis County, Missouri, USA residents ≥18 years. We asked about provider and patient-initiated cancellations or delays of appointments and pandemic-associated delays/avoidance of emergency/urgent care overall and by participant characteristics. We calculated weighted prevalence estimates by select resident characteristics.Healthcare services cancellations or delays affected ∼54% (95% CI 50.6%-57.1%) of residents with dental (31.1%, 95% CI 28.1%-34.0%) and primary care (22.1%, 95% CI 19.5%-24.6%) being most common. The highest prevalences were among those who were White, ≥65 years old, female, in fair/poor health, who had health insurance, and who had ≥1 medical condition. Delayed or avoided emergency/urgent care impacted ∼23% (95% CI 19.9%-25.4%) of residents with a higher prevalence in females than males.Healthcare use disruptions impacted a substantial proportion of residents. Future healthcare planning efforts should consider these data to minimize potential morbidity and mortality from delayed care.

The true prevalence of COVID-19 is difficult to estimate due to the absence of random population-based testing. To estimate current and past COVID-19 infection prevalence in a large urban area, we conducted a population-based survey in St. Louis County, Missouri.The population-based survey of active infection (PCR) and seroprevalence (IgG antibodies) of adults (≥18 years) was conducted through random-digit dialing and targeted sampling of St. Louis County residents with oversampling of Black residents. Infection prevalence of residents was estimated using design-based and raking weighting.Between August 17 and October 24, 2020, 1245 residents completed a survey and underwent PCR testing; 1073 residents completed a survey and underwent PCR and IgG testing or self-reported results. Weighted prevalence estimates of residents with active infection were 1.9% (95% CI, 0.4%-3.3%) and 5.6% were ever infected (95% CI, 3.3%-8.0%). Overall infection hospitalization and fatality ratios were 4.9% and 1.4%, respectively.Through October 2020, the percentage of residents that had ever been infected was relatively low. A markedly higher percentage of Black and other minorities compared to White residents were infected with COVID-19. The St. Louis region remained highly vulnerable to widespread infection in late 2020.

Background Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. Methodology All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. Principal findings Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p Conclusion IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. Trial registration Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.

Mycobacterium tuberculosis (M. tuberculosis) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other’s metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis–infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3β-hydroxysteroid dehydrogenase (3β-Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis–infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis, we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.

BACKGROUND The rapid spread of the Coronavirus disease 2019 (COVID-19) has created considerable strain on the physical and mental health of healthcare workers around the world. The effects have been acute for physician trainees—a unique group functioning simultaneously as learners and care providers with limited autonomy. OBJECTIVE To investigate the longitudinal effects of physician trainee exposure to patients being tested for COVID-19 on stress, anxiety, depression and burnout using three surveys conducted during the early phase of the pandemic. METHODS All physician trainees (N=1375) at an academic medical center were invited to participate in a web-based survey. Multivariable models were used to assess the relationship between repeated exposure to patients being tested for COVID-19 and stress, anxiety, depression and burnout. RESULTS 389 trainees completed the baseline survey (28.3%). Of these, 191 and 136 responded to the ensuing surveys. Mean stress, anxiety and burnout decreased by 21% (95% Confidence Interval (CI): -28% to -12%; P < 0.001), 25% (95% CI: -36% to -11%; P < 0.001) and 13% (95% CI: -18% to -7%; P < 0.001), respectively per survey. However, for each survey time point, there was mean increase in stress, anxiety and burnout per additional exposure: stress [24% (95% CI: +12% to +38%; P < 0.001)], anxiety [22%, (95% CI: +2% to +46%; P = 0.026)], burnout [18%, (95% CI: +10% to +28%; P < 0.001)]. For depression, the association between exposure was strongest for the third survey, where mean depression scores increased by 33% per additional exposure (95% CI: +18% to +50%; P = CONCLUSIONS Training programs should adapt to address the detrimental effects of the “pile up” of distress associated with persistent exposure through adaptive programs that allow flexibility for time off and recovery.

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, Author summary The acceptability of a new combination treatment regimen for lymphatic filariasis (ivermectin, plus DEC and albendazole, or IDA) was assessed as part of a larger community-based safety study in Fiji, Haiti, India, Indonesia and Papua New Guinea. To understand how trial participants and communities felt about the new treatment, a survey was carried out with people who had participated in the safety study receiving either the standard treatment [DEC plus albendazole (DA)] or the new treatment regimen (IDA). Focus group discussions and in-depth interviews were performed in the same communities. Results showed that there was no difference in acceptability between the DA and IDA. Adverse events and presence of filarial infection did not affect acceptability. The most important indicator associated with acceptability was country. All countries accepted the treatment regimens. Fiji had the highest acceptability scores, followed by Papua New Guinea, Indonesia, Haiti and India. Results from the qualitative research showed that study participants appreciated the professionalism of the drug delivery team and the support offered for the management of any adverse events.

We assessed the impact of three annual vs five semiannual rounds of mass drug administration (MDA) with ivermectin plus albendazole followed by praziquantel for the control or elimination of lymphatic filariasis (LF), onchocerciasis, soil-transmitted helminth (STH) infections and schistosomiasis in Lofa County, Liberia. The study started in 2012 and was interrupted in 2014 during the Ebola virus outbreak. Repeated cross-sectional surveys were conducted in individuals 5 years and older to measure infection markers. Wuchereria bancrofti antigenemia prevalences decreased from 12.5 to 1.2% (90% reduction) and from 13.6 to 4.2% (69% reduction) one year after three rounds of annual or five rounds of semiannual MDA, respectively. Mixed effects logistic regression models showed decreases in odds of antigenemia positivity were 91 and 74% at that time in the annual and semiannual treatment zones, respectively (p 0.001). Semiannual MDA was slightly more effective for reducing Onchocerca volvulus microfiladermia prevalence and at follow-up 3 were 74% (from 14.4 to 3.7%) and 83% (from 23.6 to 4.5%) in the annual and semiannual treatment zones, respectively. Both treatment schedules had similar beneficial effects on hookworm prevalence. Thus, annual and semiannual MDA with ivermectin and albendazole had similar beneficial impacts on LF, onchocerciasis, and STH in this setting. In contrast, MDA with praziquantel had little impact on hyperendemic Schistosoma mansoni in the study area. Results from a long-term follow-up survey showed that improvements in infection parameters were sustained by routine annual MDA provided by the Liberian Ministry of Health after our study endpoint.

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: Washington University School of Medicine (n=134) and Yale School of Medicine (n=49). We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza (n=54), and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV, n=22). We demonstrate that circulating markers of complement activation 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., angiopoietin-2) 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., Increased complement activation is observed in COVID-19 compared to non-COVID respiratory illness, and is a key marker of organ failure.

Background Mitochondrial 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. Methods We 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. Results Circulating 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. Conclusion These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding Washington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.

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.

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.

ImportanceHypertension is the largest contributor to the Global Burden of Disease. In Rwanda, as in most low-income and middle-income countries, an increasing prevalence of hypertension and its associated morbidity and mortality is causing major healthcare and economic impact. Understanding healthcare systems context in hypertension care is necessary.ObjectiveTo study the hypertension healthcare context as perceived by healthcare providers using the Context Assessment for Community Health (COACH) tool.DesignA cross-sectional cohort responded to the COACH questionnaire and a survey about hypertension training.SettingThree tertiary care hospitals in Rwanda.ParticipantsHealthcare professionals (n=223).Primary outcome(s) and measure(s)The COACH tool consists of 49 items with eight subscales: resources, community engagement, commitment to work, informal payment, leadership, work culture, monitoring services for action (5-point Likert Scale) and sources of knowledge (on a 0–1 scale). Four questions surveyed training on hypertension.ResultsResponders (n=223, 75% women; 56% aged 20–35 years) included nurses (n=142, 64%, midwives (n=42, 19%), primary care physicians (n=28, 13%) and physician specialists (n=11, 5%)). The subscales commitment to work, leadership, work culture and informal payment scored between 4.7 and 4.1 and the community engagement, monitoring services for action and organizational resources scored between 3.1 and 3.5. Sources of knowledge had a mean score of 0.6±0.3. While 73% reported having attended a didactic hypertension seminar in the past year, only 28% had received long-term training and 51% had ConclusionsThere is a need for increased and continuous training in Rwanda. Healthcare responders stated a commitment to work and reported supportive leadership, while acknowledging limited resources and no monitoring systems. The COACH tool provides contextual guidance to develop training strategies prior to the implementation of a sustainable hypertension care programme.

BACKGROUND: Young children listed for liver transplant have high waitlist mortality (WL), which is not fully predicted by the PELD score. METHODS: 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. RESULTS: 81.5 % candidates underwent LT, 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 god 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. CONCLUSIONS: Change in creatinine, listing status, need for RRT, time spent on LT waitlist and diagnoses were the most predictive variables.

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(1), FVC, and FEV(1)/FVC z-scores and methacholine PC(20) 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(1) (P < .0001) FVC (P < .0001) and FEV(1)/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(20) 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.

Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years. The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18–48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits. A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments. This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.

Rationale: Adverse events have limited the use of bronchial thermoplasty (BT) in severe asthma. Objectives: We sought to evaluate the effectiveness and safety of using (129)Xe magnetic resonance imaging ((129)Xe MRI) to prioritize the most involved airways for guided BT. Methods: Thirty subjects with severe asthma were imaged with volumetric computed tomography and (129)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. Measurements and Main Results: 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]; P = 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%; P = 0.009). Thirty-three percent experienced asthma exacerbations after one guided BT compared with 73% after three unguided BTs (P = 0.028). Conclusions: Results of this pilot study suggest that similar short-term improvements can be achieved with one BT treatment guided by (129)Xe MRI when compared with standard three-treatment-session BT with fewer periprocedure adverse events.

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.

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 t 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.