Citations

Abstract Background: Despite much research published on lung cancer screening, China has had no large-scale study on the missed diagnosis of lung cancer in physical examination population. We therefore did a real-world study using the current lung cancer screening guidelines to the physical examination population in China to determine the proportion of lung cancer cases that have been missed.Methods: A real-world prospective cohort study of screening, with the use of low-dose computed tomography, was conducted among people who took yearly health checkup in health management center of West China Hospital between 2006 and 2017. We respectively used current guidelines including lung cancer screening guidelines of the U.S. Preventive Services Task Force (USPSTF) and expert consensus on low dose spiral CT lung cancer screening in China. Results: In a total of 15996 participants with physical examination who completed the baseline screening, 6779 (42.4%) subjects had at least one positive finding, and 142 (2.1%) cases of lung cancer were screened positive. The false positive rate was 97.9%. Of 142 lung cancer cases detected in our study, only 9.2% met the lung cancer screening guidelines proposed by the USPSTF, and 24.4% met that of China. The rates of missed diagnosis were as high as 90.8% and 75.6% respectively. In addition, we did an in-depth analysis by gender. We found that among male lung cancer patients, the proportion of smokers was 75%, and the proportion of young people under 50 was 23.2%. Among female patients with lung cancer, the proportion of smokers was only 5.8%, and the proportion of young people under 50 was up to 33.3%.Conclusions: The rate of missed diagnosis was as high as 90.8% applying the current lung cancer screening guidelines to the physical examination population in China. Further study to determine screening guidelines for targeted populations, is warranted.

Heparin-induced thrombocytopenia (HIT) is a serious reaction to heparin treatment characterized by antibodies that recognize a complex formed between heparin and platelet factor 4 (PF4/H) and are capable of activating platelets and inducing a pro-thrombotic state. Although a high percentage of heparin-treated patients produce antibodies to PF4/H, only a subset of these antibodies are platelet-activating (pathogenic) and capable of causing HIT. We previously reported that we cloned B cells from six patients experiencing HIT and identified two types of PF4/H-binding antibodies: seven platelet-activating (PA) and 48 non-activating (NA). Comparison of the structural features in the PA, NA, and non PF4/H-binding (NB) clones showed that the length and the number of basic amino acid and tyrosine residue in the heavy chain complementarity determining region 3 (HCDR3) were significantly different, and was in the order of PA>NA>NB. Most significantly, the seven platelet-activating antibodies each have one of the two pathogenic motifs: RX1-2 R/KX1-2 R/H and YYYYY in an unusually long HCDR3 (≥ 20 residues). In the current study, we attempt to understand the origin of the B cells that produce the PA and NA antibodies and the nature of the immune response in HIT through analyzing somatic hypermutation and biological property of such antibodies. Longer HCDR3 and more basic Aas and Tyr residues in the HCDR3 are features of autoreactive and polyreactive antibodies. With this in mind, we tested PA and NA clones in a standard antinuclear antibody (ANA) assay and found that these clones were significantly more reactive than NB antibodies, and the plasma of HIT patients were significantly more reactive than normal plasma (Figure1). We then compared reactions of PA, NA and NB clones against a group of self and foreign antigens commonly used in polyreactivity assays: dsDNA, ssDNA, LPS, insulin, and keyhole limpet hemocyanin (KLH). About 90% of PA and NA clones were reactive to at least two antigens, this was true of only 20% of the NB clones, and the latter is consistent with the frequency of polyreactive clones in the IgG+ B cells (Figure2). Taken together, these data indicate that PA and NA antibodies are largely polyreactive. We then investigated the development of the PA and NA B cells through analyzing somatic hypermutation in the antibodies. Through analyzing the HCDR3 nucleotide insertion, trimming and VDJ segment usage, we found that longer HCDR3 typical of PF4/H-binding clones and the RKH and Y5 motifs identified in PA clones were the result of original recombination not somatic hypermutation. Consistently, the average number of nucleotide mutations in the VH genes of the binding clones was lower (PA and NA, 9.4 ± 9.5) compared to that of peripheral blood IgG+ memory B cells in healthy subjects (~18) (Figure3). Total mutation frequency in the VH and Vk CDRs of the PF4/H-binding PA and NA clones was comparable to that of the framework regions. This finding contrasts with findings made in peripheral blood IgG+ memory B cells of healthy subjects showing that the mutation frequencies are much higher in the CDRs than in the FRs of VH. Taken together, these findings suggest that affinity maturation plays a limited role in the evolution PF4/H-binding antibodies during the immune response that leads to HIT. In this study, we showed thay PF4/H-binding PA and NA IgGs are largely polyreactive antibodies and contain lower levels of mutations compared to IgG+ memory B cells. B1 and MZ B cells are innate B cells that are main producers of polyreactive natural antibodies and can respond to toll-like receptor signaling, quickly differentiate into antibody-secreting cells, and undergo IgG class switch extrafollicularly. Polyreactivity identified in the PF4/H-binding PA and NA IgGs supports the possibility that human B cells producing PF4/H-binding antibodies are innate B cells akin to MZ B cells shown to be a source of PF4/H antibodies in mice. A mutation rate lower than that of IgG+ memory cells in the PF4/H-binding IgGs is also consistent with an extrafollicular response typical of innate B cells. These observations would help to improve our understanding of the immunological responses and B cell origin in HIT patients. Disclosures Padmanabhan: Retham Technologies: Current equity holder in private company; Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees; Versiti Blood Research Institute: Patents & Royalties.

Abstract The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-κB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. Significance: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.

In 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate an Objective Structured Clinical Examination (OSCE) into its initial certification examination system. Previously, the ABA’s staged examination system consisted of 2 written examinations (the BASIC and ADVANCED examinations) and the Standardized Oral Examination (SOE). The OSCE and the existing SOE are now 2 separate components of the APPLIED Examination. This report presents the results of the first-year OSCE administration. A total of 1410 candidates took both the OSCE and the SOE in 2018. Candidate performance approximated a normal distribution for both the OSCE and the SOE, and was not associated with the timing of the examination, including day of the week, morning versus afternoon session, and order of the OSCE and the SOE. Practice-based Learning and Improvement was the most difficult station, while Application of Ultrasonography was the least difficult. The correlation coefficient between SOE and OSCE scores was 0.35 ([95% confidence interval {CI}, 0.30–0.39]; P < .001). Scores for the written ADVANCED Examination were modestly correlated with scores for the SOE ( r = 0.29 [95% CI, 0.25–0.34]; P < .001) and the OSCE ( r = 0.15 [95% CI, 0.10–0.20]; P < .001). Most of the candidates who failed the SOE passed the OSCE, and most of the candidates who failed the OSCE passed the SOE. Of the 1410 candidates, 77 (5.5%) failed the OSCE, 155 (11.0%) failed the SOE, and 25 (1.8%) failed both. Thus, 207 (14.7%) failed at least 1 component of the APPLIED Examination. Adding an OSCE to a board certification examination system is feasible. Preliminary evidence indicates that the OSCE measures aspects of candidate abilities distinct from those measured by other examinations used for initial board certification.

Background Weak alar cartilage and lack of soft tissue on the cleft side are considered to be the main critical factors leading to the asymmetry of bilateral nostrils. The costal cartilage can provide strong structural support and can be used to maintain long-term stability of nostril shape after surgical correction. With the advancement in rhinoplasty techniques, the application and understanding of costal cartilage in cleft lip nasal deformity is still on going. Herein, we present our technique of applying costal cartilage to provide nostril support and correct asymmetry in Asian patients with unilateral secondary cleft lip nasal deformity. Methods Ninety-seven patients who underwent nostril asymmetry correction from January 1, 2013, to October 31, 2018, were analyzed retrospectively. Modified integrative alar cartilage strut and diced nostril augmentation with costal cartilage were implemented to improve the collapsed and flat cleft-side nostril. The release and restoration of muscle and bone were also performed when required. Surgical outcomes were analyzed based on the comparison of nostril parameters, the shape and contour, and symmetry of bilateral nostrils after surgery. During postoperative follow-up, the patients' satisfactions with the corrective outcomes were also investigated. Results All patients received the corrective operations with complete survival of all implanted cartilages. The nostril width was narrower in postoperative group (P < 0.05). The nostril height and long axis angle were higher postoperatively (P < 0.05). After correction, the proportion of moderate type increased from 13.4% to 80.4%, whereas the proportion of horizontal type decreased from 86.6% to 17.5%. The symmetry score on the nostril parameters manifested the rate of high score (AS >3) in postoperative groups were 84.5%, 93.8%, and 87.6% for width, height, and angle of the long axis, respectively. They were higher compared with those of preoperative group (0%). More than 95% of the patients were satisfied with the overall aesthetic outcome of the surgery. Conclusions Through ameliorating its constructive technology and optimizing its filling form, the modified use of costal cartilage displayed excellent correction effects in the width, height, and long axis angle asymmetry of Asian patients' nostril. Precise and comprehensive rhinoplasty technique is the cornerstone for achieving satisfactory long-term aesthetic outcomes, especially in severe cases, such as secondary cleft lip nasal deformity.

Objectives: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. Design: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. Setting: Thirty-three hospital sites in the United States ( n = 32) and Jordan ( n = 1). Patients: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. Interventions: None. Measurements and Main Results: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851–5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4–18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16–1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. Conclusions: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Background Bronchopleural fistula (BPF) is a dreaded complication of pulmonary resection. For high-risk patients, bronchial stump coverage with vascularized tissue has been recommended. The goal of this study was to report our experience with intrathoracic muscle transposition for bronchial stump coverage. Methods A retrospective review of all patients who underwent intrathoracic muscle flap transposition as a prophylactic measure at our institution between 1990 and 2010 was conducted. Demographics, surgical characteristics, and complication rates were abstracted and analyzed. Results A total of 160 patients were identified. The most common lung resections performed were pneumonectomy (n = 69, 43%) and lobectomy (n = 60, 38%). A total of 168 flaps were used where serratus anterior was the most common flap (n = 136, 81%), followed by intercostal (n = 14, 8%), and latissimus dorsi (n = 12, 7%). Ten patients (6%) developed BPF, and empyema occurred in 13 patients (8%). Median survival was 20 months, and operative mortality occurred in 7 patients (4%). Conclusions Reinforcement of the bronchial closure with vascularized muscle is a viable option for potentially decreasing the incidence of BPF in high-risk patients. Further randomized studies are needed to determine the efficacy of this technique for BPF prevention.