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

Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies1-7. Individuals who have recovered from COVID-19 have a substantially lower risk of reinfection with SARS-CoV-28-10. Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived11-13. Here we show that in convalescent individuals who had experienced mild SARS-CoV-2 infections (n = 77), levels of serum anti-SARS-CoV-2 spike protein (S) antibodies declined rapidly in the first 4 months after infection and then more gradually over the following 7 months, remaining detectable at least 11 months after infection. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. We show that S-binding BMPCs are quiescent, which suggests that they are part of a stable compartment. Consistently, circulating resting memory B cells directed against SARS-CoV-2 S were detected in the convalescent individuals. Overall, our results indicate that mild infection with SARS-CoV-2 induces robust antigen-specific, long-lived humoral immune memory in humans.

Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors.

BACKGROUND: Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation. METHODS: In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 µg per hour for a minimum of 12 hours) or saline placebo. The primary outcome was transplantation of the donor heart; graft survival at 30 days after transplantation was a prespecified recipient safety outcome. Secondary outcomes included weaning from vasopressor therapy, donor ejection fraction, and number of organs transplanted per donor. RESULTS: Of the 852 brain-dead donors who underwent randomization, 838 were included in the primary analysis: 419 in the levothyroxine group and 419 in the saline group. Hearts were transplanted from 230 donors (54.9%) in the levothyroxine group and 223 (53.2%) in the saline group (adjusted risk ratio, 1.01; 95% confidence interval [CI], 0.97 to 1.07; P = 0.57). Graft survival at 30 days occurred in 224 hearts (97.4%) transplanted from donors assigned to receive levothyroxine and 213 hearts (95.5%) transplanted from donors assigned to receive saline (difference, 1.9 percentage points; 95% CI, -2.3 to 6.0; P<0.001 for noninferiority at a margin of 6 percentage points). There were no substantial between-group differences in weaning from vasopressor therapy, ejection fraction on echocardiography, or organs transplanted per donor, but more cases of severe hypertension and tachycardia occurred in the levothyroxine group than in the saline group. CONCLUSIONS: In hemodynamically unstable brain-dead potential heart donors, intravenous levothyroxine infusion did not result in significantly more hearts being transplanted than saline infusion. (Funded by Mid-America Transplant and others; ClinicalTrials.gov number, NCT04415658.).

Azithromycin therapy in infants hospitalized for respiratory syncytial virus bronchiolitis: Airway matrix metalloproteinase-9 levels and subsequent recurrent wheeze.

BACKGROUND: Early life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits. OBJECTIVE: To investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW). METHODS: A total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months. RESULTS: Upper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively). CONCLUSION: Azithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV. TRIAL REGISTRATION: This study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).

Risk Factors for Nontuberculous Mycobacteria Infections in Solid Organ Transplant Recipients: A Multinational Case-Control Study.

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.

The salivary and nasopharyngeal microbiomes are associated with SARS-CoV-2 infection and disease severity.

Emerging evidence suggests the oral and upper respiratory microbiota may play important roles in modulating host immune responses to viral infection. As the host microbiome may be involved in the pathophysiology of coronavirus disease 2019 (COVID-19), we investigated 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. Severe acute respiratory syndrome coronavirus 2 (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. Oral Bifidobacterium, Lactobacillus, and Solobacterium 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 and monocyte chemoattractant protein-1. Our results suggest COVID-19 disease severity is associated with the relative abundance of certain bacterial taxa.

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

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.

Quantitative CT Characteristics of Cluster Phenotypes in the Severe Asthma Research Program Cohorts.

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; P < .001). Lower whole-lung Jacobian and ADI values were associated with greater cluster severity. Compared to cluster 1, cluster 5 lung expansion was 31% smaller (Jacobian in SARP III cohort: 2.31 ± 0.6 vs 1.61 ± 0.3, respectively, P < .001) and 34% more isotropic (ADI in SARP III cohort: 0.40 ± 0.1 vs 0.61 ± 0.2, P < .001). Within-lung Jacobian and ADI SDs decreased as severity worsened (Jacobian SD in SARP III cohort: 0.90 ± 0.4 for cluster 1; 0.79 ± 0.3 for cluster 2; 0.62 ± 0.2 for cluster 3; 0.63 ± 0.2 for cluster 4; and 0.41 ± 0.2 for cluster 5; P < .001). Conclusion Quantitative CT assessments of the degree and intraindividual regional variability of lung expansion distinguished between well-established clinical phenotypes among participants with asthma from the Severe Asthma Research Program study. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Effects of Persistent Exposure to COVID-19 on Mental Health Outcomes Among Trainees: a Longitudinal Survey Study.

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. DESIGN: Longitudinal survey study. PARTICIPANTS: All physician trainees (N = 1375) at an academic medical center. MAIN MEASURE: Assess the relationship between repeated exposure to patients being tested for COVID-19 and stress, anxiety, depression, and burnout. KEY RESULTS: Three hundred eighty-nine trainees completed the baseline survey (28.3%). Of these, 191 and 136 completed 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)], and 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 < 0.001). CONCLUSIONS: Training programs should adapt to address the detrimental effects of the "pileup" of distress associated with persistent exposure through adaptive programs that allow flexibility for time off and recovery.

Outcomes Analyses of Pediatric Acute Liver Failure Subjects Listed for Liver Transplantation.

BACKGROUND: We characterized recent outcomes in US pediatric acute liver failure (PALF) subjects listed for liver transplantation (LT) using the Scientific Registry of Transplant Recipients (SRTR) database. METHODS: Pediatric subjects listed for LT from 2002 to 2015 were assigned to the "PALF" group based on status 1/1A listing, INR >2, no hepatic artery thrombosis, and no primary graft nonfunction (N = 397). Subjects were assigned to the "non-PALF" group if listed with any status other than 1/1A (N = 4509). RESULTS: The PALF group had more infants <3 months of age and males at listing for LT compared to the non-PALF group. Two-thirds of PALF subjects had an indeterminate etiology. LT waitlist survival was significantly worse in the PALF group compared to the non-PALF group. Likelihood of removal from the LT waitlist for being "too sick" was higher, while that of removal for "spontaneous recovery" was lower in PALF subjects. Post-LT short-term (30 days) and long-term (60 months) outcomes were also significantly worse in PALF versus non-PALF subjects. PALF subjects who underwent living-donor-liver-transplant (LDLT) had similar LT waitlist times and post-LT survival compared to those undergoing deceased-donor-liver-transplant (DDLT). Over the study period, we observed a decreased number of liver transplants, and increase in LT waitlist- and short-term post-LT-survival in PALF subjects. CONCLUSION: LT waitlist and post-LT outcomes are worse in PALF subjects compared to non-PALF subjects. PALF subjects who undergo LDLT have similar waitlist times and post-LT outcomes compared to those undergoing DDLT.

Employment Loss and Food Insecurity - Race and Sex Disparities in the Context of COVID-19.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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

BACKGROUND: Currently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function. OBJECTIVES: We aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma. METHODS: 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. RESULTS: Greater baseline wall area percent (ß = -0.15 [95% CI = -0.26 to -0.05]; P < .01), hyperinflation percent (ß = -0.25 [95% CI = -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal ß = 10.64 [95% CI = 3.79-17.49]; P < .01; posterior-anterior ß = -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. CONCLUSIONS: 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.

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

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 .).

Assessment of serological assays for identifying high titer convalescent plasma.

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.

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

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 FEV1 , FVC, and FEV1 /FVC z-scores and methacholine PC20 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 FEV1 (P < .0001) FVC (P < .0001) and FEV1 /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. PC20 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.

Single-Session Bronchial Thermoplasty Guided by 129Xe Magnetic Resonance Imaging. A Pilot Randomized Controlled Clinical Trial.

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 129Xe magnetic resonance imaging (129Xe MRI) to prioritize the most involved airways for guided BT.Methods: Thirty subjects with severe asthma were imaged with volumetric computed tomography and 129Xe 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 129Xe MRI when compared with standard three-treatment-session BT with fewer periprocedure adverse events.

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?

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.

Risk factors associated with physician trainee concern over missed educational opportunities during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic resulted in a transformation of clinical care practices to protect both patients and providers. These changes led to a decrease in patient volume, impacting physician trainee education due to lost clinical and didactic opportunities. We measured the prevalence of trainee concern over missed educational opportunities and investigated the risk factors leading to such concerns. METHODS: All residents and fellows at a large academic medical center were invited to participate in a web-based survey in May of 2020. Participants responded to questions regarding demographic characteristics, specialty, primary assigned responsibility during the previous 2 weeks (clinical, education, or research), perceived concern over missed educational opportunities, and burnout. Multivariable logistic regression was used to assess the relationship between missed educational opportunities and the measured variables. RESULTS: 22% (301 of 1375) of the trainees completed the survey. 47% of the participants were concerned about missed educational opportunities. Trainees assigned to education at home had 2.85 [95%CI 1.33-6.45] greater odds of being concerned over missed educational opportunities as compared with trainees performing clinical work. Trainees performing research were not similarly affected [aOR = 0.96, 95%CI (0.47-1.93)]. Trainees in pathology or radiology had 2.51 [95%CI 1.16-5.68] greater odds of concern for missed educational opportunities as compared with medicine. Trainees with greater concern over missed opportunities were more likely to be experiencing burnout (p = 0.038). CONCLUSIONS: Trainees in radiology or pathology and those assigned to education at home were more likely to be concerned about their missed educational opportunities. Residency programs should consider providing trainees with research or at home clinical opportunities as an alternative to self-study should future need for reduced clinical hours arise.

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

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.

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

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.

The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results.

PURPOSE: Evaluation of the clinician's role in the optimal interpretation of clinical exome sequencing (ES) results. METHODS: Retrospective chart review of the first 155 patients who underwent clinical ES in our Exome Clinic and direct interaction with the ordering geneticist to evaluate the process of interpretation of results. RESULTS: The most common primary indication was neurodevelopmental problems (~66%), followed by multiple congenital anomalies (~10%). Based on sequencing data, the overall diagnostic yield was 36%. After assessment by the medical geneticist, incorporation of detailed phenotypic and molecular data, and utilization of additional diagnostic modalities, the final diagnostic yield increased to 43%. Seven patients in our cohort were included in initial case series that described novel genetic syndromes, and 23% of patients were involved in subsequent research studies directly related to their results or involved in efforts to move beyond clinical ES for diagnosis. Clinical management was directly altered due to the ES findings in 12% of definitively diagnosed cases. CONCLUSIONS: Our results emphasize the usefulness of ES, demonstrate the significant role of the medical geneticist in the diagnostic process of patients undergoing ES, and illustrate the benefits of postanalytical diagnostic work-up in solving the "diagnostic odyssey." Genet Med advance online publication 02 March 2017.