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I., Executive Summary: BACKGROUND: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR-RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR-RS-2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence-based findings of the document., Methods: ICAR-RS presents over 180 topics in the forms of evidence-based reviews with recommendations (EBRRs), evidence-based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary., Results: ICAR-RS-2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence-based management algorithm is provided., Conclusion: This ICAR-RS-2021 executive summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS., (© 2021 ARS-AAOA, LLC.)

Plastics have enormous impacts to every aspect of daily life including technology, medicine and treatments, and domestic appliances. Most of the used plastics are thrown away by consumers after a single use, which has become a huge environmental problem as they will end up in landfill, oceans and other waterways. These plastics are discarded in vast numbers each day, and the breaking down of the plastics from micro- to nano-sizes has led to worries about how toxic these plastics are to the environment and humans. While, there are several earlier studies reported the effects of micro- and nano-plastics have on the environment, there is scant research into their impact on the human body at subcellular or molecular levels. In particular, the potential of how nano-plastics move through the gut, lungs and skin epithelia in causing systemic exposure has not been examined thoroughly. This review explores thoroughly on how nanoplastics are created, how they behave/breakdown within the environment, levels of toxicity and pollution of these nanoplastics, and the possible health impacts on humans, as well as suggestions for additional research. This paper aims to inspire future studies into core elements of micro- and nano-plastics, the biological reactions caused by their specific and unusual qualities.

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and an intolerance of medications that inhibit cyclooxygenase-1. Patients with AERD have more severe upper and lower respiratory tract disease than do aspirin-tolerant patients with CRSwNP. A dysregulation in arachidonic acid metabolism is thought to contribute to the enhanced sinonasal inflammation in AERD., Objective: Our aim was to utilize an unbiased approach investigating arachidonic acid metabolic pathways in AERD., Methods: Single-cell RNA sequencing (10× Genomics, Pleasanton, Calif) was utilized to compare the transcriptional profile of nasal polyp (NP) cells from patients with AERD and patients with CRSwNP and map differences in the expression of select genes among identified cell types. Findings were confirmed by traditional real-time PCR. Lipid mediators in sinonasal tissue were measured by mass spectrometry. Localization of various proteins within NPs was assessed by immunofluorescence., Results: The gene encoding for 15-lipooxygenase (15-LO), ALOX15, was significantly elevated in NPs of patients with AERD compared to NPs of patients with CRSwNP (P < .05) or controls (P < .001). ALOX15 was predominantly expressed by epithelial cells. Expression levels significantly correlated with radiographic sinus disease severity (r = 0.56; P < .001) and were associated with asthma. The level of 15-oxo-eicosatetraenoic acid (15-Oxo-ETE), a downstream product of 15-LO, was significantly elevated in NPs from patients with CRSwNP (27.93 pg/mg of tissue) and NPs from patients with AERD (61.03 pg/mg of tissue) compared to inferior turbinate tissue from controls (7.17 pg/mg of tissue [P < .001]). Hydroxyprostaglandin dehydrogenase, an enzyme required for 15-Oxo-ETE synthesis, was predominantly expressed in mast cells and localized near 15-LO + epithelium in NPs from patients with AERD., Conclusions: Epithelial and mast cell interactions, leading to the synthesis of 15-Oxo-ETE, may contribute to the dysregulation of arachidonic acid metabolism via the 15-LO pathway and to the enhanced sinonasal disease severity observed in AERD., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Cancer defects requiring anterior mediastinal tracheostomy (AMT) are complex, often accompanied by tracheo-laryngeal and pharyngeal defects with exposure of the great vessels and mediastinal cavity. The trachea has to be mobilised and exteriorised as an end-tracheostome through the anterior chest. A well-vascularised flap that can resurface skin defects, obliterate dead space and allow maturation of a reliable anterior mediastinal tracheostome is required. We describe a modification of using a centrally fenestrated bipedicled chimeric anterolateral thigh flap (ALT) to address these challenges., Methods: A free chimeric bipedicled ALT flap was designed. The skin defect was resurfaced by a vertically-oriented skin paddle. Two chimeric muscle components were used to partition the mediastinum and the great vessels of the neck from the tracheostome. The mediastinal trachea was mobilised and matured through a centrally-fenestrated opening in the flap. Layered fascial sutures were employed to minimize dehiscence., Results/complications: Two patients with AMT underwent the modified ALT. No major complications such as flap-tracheostomy dehiscence occurred. One patient had a small peripheral demarcation of the flap which required revision and secondary closure., Conclusion: The bipedicled design of the modified ALT flap provided robust blood supply to the central fenestration through dual perforators, avoiding flap-tracheostomy separation. The chimeric muscle components obliterate dead space and protect the great vessels of the neck and mediastinum. The thin pliable nature of the anterolateral thigh skin also allowed for tensionless inset of the trachea., Competing Interests: None declared., (© 2021 The Authors. Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.)

Background: In comminuted facial fractures, peri-operative use of 3D-printed life size models is increasingly a useful adjunct. It allows for preoperative surgical rehearsal and plate bending, to achieve anatomical reduction with reduced operative time and cost. One problem encountered is difficulty contouring the fixation plate whilst maintaining the relative spatial orientation of comminuted fragments. This paper shares an effective method of overcoming this problem., Methods: All comminuted facial fracture patients underwent counselling for 3D printing. Pre-printing thresholding and segmentation of each fragment (as directed by the surgeon) were done by the radiologist and the engineering team, using the multi-slice CT Face DICOM data. Life-size 3D-resin models of the fractures were printed. Fast-acting medium consistency cyanoacrylate glue (Zap-A-Gap Ⓡ ) and miniplates were used to assemble the printed model segments in 'anatomic reduction'. Aerosolized alcohol accelerator facilitated immediate glue curing, providing a stable model. The plates were adapted over this restored neonative 3D construct with bending inserts, sterilized and used intraoperatively. The 3D model was used to guide the operative sequence. Intraoperative CT was used in select cases to confirm anatomic reduction., Results/complications: All patients ( n  = 5) had comminuted fractures in at least one of the bony units (mandible, maxilla or orbits) and one was a pan-facial fracture case. 3D printed models aided fracture reduction and fixation, whilst avoiding the guesswork in ascertaining the contour of the mandibular arch. In addition, the pre-contoured mandible plates restored premorbid occlusion and projection, without the need for long-term archbars in all cases. Operative time was estimated to be reduced by 0.5-1 h. Resident teaching was enhanced by this approach., Conclusion: The application of medium consistency fast-acting cyanoacrylate glue and miniplates facilitated the creation of the premorbid facial skeletal model and allowed pre-bending of the plates, thus saving operative time and cost., Competing Interests: N/a., (© 2021 The Author(s). Published by Elsevier Ltd on behalf of British Association of Plastic, Reconstructive and Aesthetic Surgeons.)

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro . Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gharanei, Fishwick, Peter Durairaj, Jin, Siamantouras, Liu, Straube, Lucas, Weston, Rantakari, Salmi, Jalkanen, Brosens and Tan.)

Hepatic artery (HA) complications after liver transplant (LT) can lead to biliary complications, graft failure, and mortality. Although microsurgery has been established to improve anastomotic outcomes, it prolongs surgical time and has not reached widespread adoption at all transplant centers. We investigated the incidences of arterial, biliary complications and outcomes after using microsurgery to anastomose HA during LT. Retrospective cohort of consecutive LT performed from 2006 to 2018 was reviewed for operative details and postoperative outcomes. Cox-regression models were used to investigate the relationship between variables and outcomes. Eighty (62.5%) LTs (Group 1) were performed without and compared with 48 (Group 2) with microsurgical anastomosis of HA. Both groups were comparable in terms of arterial and biliary anastomoses performed. Incidence of early HA thrombosis was similar (6.2% vs 2.1%, P = .28). Group 2 had lower incidence of short- and long-term arterial complications, especially amongst living donor liver transplantations (LDLT) (5.3% vs 35.0%, P = .022). On multivariate analysis, microsurgery was associated with lower risk (hazard ratio [HR] 0.09, 95% confidence interval [CI] 0.01-0.71) of, and LDLT had higher risk (HR 4.23, 95% CI 1.46-12.27) of arterial complications. Biliary complications were associated with LDLT (HR 3.91, 95% CI 1.30-11.71) and dual biliary anastomoses (HR 5.26, 95% CI 1.15-24.08) but not with occurrence of HA complications. Worse patient survival was associated with the occurrence of any HA complication (HR 4.11, 95% CI 1.78-9.48). Hepatic arterial complications can be reduced using microsurgical techniques for the anastomosis, resulting in improved patient survival outcomes after liver transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lymphedema is defined as the abnormal accumulation of interstitial fluid in subcutaneous tissues resulting from cancer, cancer treatment (surgery and/or radiotherapy), infection, inflammatory disorders, obesity, and hereditary syndromes. Surgical management of lymphedema can be broadly classified into two categories, reductive surgical techniques such as direct excision, suction assisted protein lipectomy (SAPL) or radical reduction with perforator preservation (RRPP); and physiological surgical procedures such as lymphaticovenous anastomosis (LVA) and vascularised lymph node transfer (VLNT). These techniques and their various combinations were evaluated. The results revealed patients with reversible lymphedema (ISL stage I, mild severity) benefit most from physiological procedures (LVA or VLNT) which can reduce the chance of disease progression to the chronic, solid phase. Reductive techniques such as SAPL, RPPP, or direct excision procedures should be reserved for patients with advanced - severe lymphedema (ISL stages II and especially stage III) as the surgical treatment of choice. In this study, current literature on the surgical treatment of lower extremity lymphedema is reviewed and discussed in conjunction with authors' clinical experiences. An algorithm is presented, based on clinical evidence and experience which aims to provide a structured approach to managing lower limb lymphedema., (Copyright © 2020. Published by Elsevier Taiwan LLC.)

Objectives/hypothesis: Otolaryngologic symptoms of obstructive sleep apnea (OSA) and their diagnostic utility are not well studied. We aimed to elucidate the prevalence of otolaryngologic symptoms among patients being evaluated for OSA. Given findings that the Reflux Symptom Index (RSI) was strongly associated with OSA status, we evaluated the diagnostic utility of the RSI for predicting OSA status., Study Design: Cross-sectional., Methods: We recruited 101 adults presenting for ambulatory polysomnograms to the Northwestern Sleep Disorders Center from July 2017 to July 2018. The Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Leicester Cough Questionnaire (LCQ), RSI, Gastroesophageal Reflux Disease Questionnaire, Sino-Nasal Outcome Test-22, Nasal Obstruction Symptom Evaluation, Eustachian Tube Dysfunction Questionnaire 7, and Headache Impact Test were administered. Polysomnogram results were subsequently obtained. Patients with OSA (apnea-hypopnea index ≥ 5) and without OSA were compared., Results: Of the 101 participants, 98 had valid sleep study results. Of those, 72 were diagnosed with OSA and 26 were not. The two groups differed significantly in age and body mass index (BMI). Of the questionnaires, only the RSI and LCQ means differed significantly, with worse symptoms in the OSA group (P = .003 and .014, respectively). Upon univariate regression, age, BMI, and RSI were associated with OSA status. Using regression coefficients, a clinical score of 2 (RSI) + 1.5 (BMI) + age yielded a diagnostic model (C-statistic = 0.807, P < .001). A threshold score of 104.21 was 76.4% sensitive and 73.1% specific., Conclusions: Patients with OSA have worse symptoms of laryngopharyngeal reflux as measured by the RSI. The addition of the RSI to the recognized factors of age and BMI improves diagnostic utility for OSA., Level of Evidence: 2 Laryngoscope, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Patient Satisfaction (PS) is a commonly used metric in health care settings to assess the quality of care given by physicians. Monitoring physicians in this way may impact physician quality of life. Studies evaluating this impact are not available. This study sought to examine the physician experience of measuring PS among practicing otolaryngologists., Methods: Using an online survey platform, a 34-item survey was given to practicing otolaryngologists through email distribution. The survey included questions about physician, practice and patient demographics, as well as inquiries regarding the way in which PS was measured and how it affected physician work and personal life. Data from these questions were reviewed and analyzed., Results: 174 otolaryngologists responded to the survey. A majority of physicians' (55.3%) PS scores had been tracked with 89.9% reporting being tracked for a length of at least 1 year. PS scores for individual physicians were noted to be inconsistent and vary significantly between reports. Measuring patient satisfaction led to increased occupational stress, yet most physicians (63.8%) felt the monitoring did not lead to improvements in their practice. Some physicians (36.2%) reported that the collection of patient satisfaction scores had negatively influenced the way they practiced medicine, including the pressure to order superfluous tests or to prescribe unnecessary medications., Conclusion: Overall, physicians are negatively affected by the tracking of patient satisfaction scores. Occupational stress caused by the collection of patient satisfaction scores may contribute to physician burnout., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Identification of one's status as a BRCA1/2 pathogenic variant carrier often marks the start of navigating challenging decisions related to cancer risk management and result disclosure. Carriers report unmet informational needs, but studies have yet to explore the specific aspects of and how best to fulfill these needs. This study aims to explore the informational needs of BRCA1/2 pathogenic variant carriers in Asia to inform for the design of educational materials to support risk management decision-making., Methods: Semi-structured in-depth interviews were conducted with two male and 22 female English-speaking BRCA1/2 pathogenic variant carriers, aged 29-66 years, identified through the Cancer Genetics Service at the National Cancer Centre Singapore. A grounded theory approach with thematic analysis was undertaken to extract dominant themes., Results: Four themes were identified: (i) proactive online information seeking behaviors (ii) personalized informational needs; (iii) challenges in sharing the results; and (iv) lack of genetic awareness., Discussion: Participants highlight challenges with sharing their result arising from significant post-result informational needs, which have manifested into proactive online information-seeking behaviors. They desire for an online source of information, where content is personalized, reliable and local. Participants foresee the potential of an online resource to raise genetic awareness. This suggests the use of a culturally tailored online-based genetics resource, to promote result disclosure, empower risk-management decisions and raise genetic literacy rates., Supplementary Information: Supplementary information accompanies this paper at 10.1186/s13053-020-00154-x., Competing Interests: Competing interestsAll other authors declare no conflicts of interest., (© The Author(s) 2020.)

Analysis of circulating cell-free DNA (cfDNA) has opened new opportunities for characterizing tumour mutational landscapes with many applications in genomic-driven oncology. We developed a customized targeted cfDNA sequencing approach for breast cancer (BC) using unique molecular identifiers (UMIs) for error correction. Our assay, spanning a 284.5 kb target region, is combined with a novel freely-licensed bioinformatics pipeline that provides detection of low-frequency variants, and reliable identification of copy number variations (CNVs) directly from plasma DNA. We first evaluated our pipeline on reference samples. Then in a cohort of 35 BC patients our approach detected actionable driver and clonal variants at low variant frequency levels in cfDNA that were concordant (77%) with sequencing of primary and/or metastatic solid tumour sites. We also detected ERRB2 gene CNVs used for HER2 subtype classification with 80% precision compared to immunohistochemistry. Further, we evaluated fragmentation profiles of cfDNA in BC and observed distinct differences compared to data from healthy individuals. Our results show that the developed assay addresses the majority of tumour associated aberrations directly from plasma DNA, and thus may be used to elucidate genomic alterations in liquid biopsy studies.

Background: Currently, volunteers and/or anatomical models are used for teaching oncoplastic surgery marking. However, as the breast is an intimate organ, recruiting volunteers is difficult, and the available droopy breast models have limitations. We evaluated the feasibility of a novel Marking Breast Oncoplastic Surgery Simulator (MBOSS) for the teaching of marking., Methods: Breast/plastic surgeons/trainees, grouped according to their oncoplastic experience, were randomized to MBOSS or volunteer. All had a pre-test evaluation prior to receiving hands-on training in inverted T mammoplasty marking in their randomized group, followed by an assessment of their marking skills, by an examiner blinded to their group assignment. All participants then underwent post-test and course evaluations, and those who used MBOSS for training, also evaluated MBOSS realism. Learning outcomes between the two groups were compared using the Kirkpatrick educational model., Results: Forty participants were enrolled. Demographics, baseline oncoplastic experience and pre-test results were comparable between the MBOSS and volunteer groups. For Kirkpatrick level 1 satisfaction outcomes, the two groups did not differ significantly. For level 2 knowledge assessment, MBOSS post-test scores were significantly higher (P=0.0471). For level 3 skill application and level 4 organizational impact evaluated 6 months post course, there were no significant differences between the groups. Although MBOSS may not mimic the breast completely, 95% of MBOSS-trained participants rated MBOSS as a good training tool and 85% would use MBOSS instead of a volunteer., Conclusions: MBOSS learning outcomes are comparable to outcomes using volunteers, making MBOSS an alternative for teaching oncoplastic surgery marking., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-476). GHL received Academic Medicine Education Institute (AM.EI) education grant 2018 for the conduct of the study. The other authors have no conflicts of interest to declare., (2020 Gland Surgery. All rights reserved.)

The rapid global spread of the coronavirus disease (COVID-19) has inflicted significant health and socioeconomic burden on affected countries. As positive cases continued to rise in Malaysia, public health laboratories experienced an overwhelming demand for COVID-19 screening. The confirmation of positive cases of COVID-19 has solely been based on the detection of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) using real-time reverse transcription polymerase chain reaction (qRT-PCR). In efforts to increase the cost-effectiveness and efficiency of COVID-19 screening, we evaluated the feasibility of pooling clinical Nasopharyngeal/Oropharyngeal (NP/OP) swab specimens during nucleic acid extraction without a reduction in sensitivity of qRT-PCR. Pools of 10 specimens were extracted and subsequently tested by qRT-PCR according to the WHO-Charité protocol. We demonstrated that the sample pooling method showed no loss of sensitivity. The effectiveness of the pooled testing strategy was evaluated on both retrospective and prospective samples, and the results showed a similar detection sensitivity compared to testing individual sample alone. This study demonstrates the feasibility of using a pooled testing strategy to increase testing capacity and conserve resources, especially when there is a high demand for disease testing., Competing Interests: The authors have declared that no competing interests exist.

In the setting of autologous breast reconstruction, achieving an aesthetic outcome through shaping of the flap is of the upmost importance. We describe the abdominal flap folding technique of 'coning' and the indications. We define 'coning' as the technique of folding the abdominal flap in a circular fashion to create a conical breast mound, with the line of fusion forming a pillar of tissue for structural integrity. A retrospective study of 34 patients undergoing unilateral muscle-sparing TRAM flap was performed. Of these patients, the majority (79.4%) underwent immediate reconstruction, with the thoracodorsal vessels largely acting as the recipients (94.1%). Three (8.8%) patients were noted to have a contour defect secondary to incomplete folding of the flap. Two (5.9%) patients had partial skin envelope necrosis. One patient had 50% flap loss, requiring return to theatre for excision. In conclusion, coning was used exclusively in the muscle-sparing TRAM flap. This cuff of muscle protected the pedicle during folding through cushioning the perforators at their most vulnerable points. This technique allowed for muscle cuff harvest whilst minimising anterior sheath sacrifice. Coning achieved long-term maintenance of shape, volume and projection., Competing Interests: None of the authors has a financial interest in any of the products, devices or drugs mentioned in this manuscript., (© 2020 The Authors.)

Purpose: Suboptimal adherence to tyrosine kinase inhibitors (TKIs) contributes to poor clinical outcomes in chronic myeloid leukemia (CML). This randomised controlled trial (RCT) aimed to evaluate the impact of a medication management service (MMS) on adherence to TKIs and clinical outcomes., Methods: A parallel RCT was conducted in two hospitals in Malaysia, where 129 CML patients were randomised to MMS or control (usual care) groups using a stratified 1:1 block randomisation method. The 6-month MMS included three face-to-face medication use reviews, CML and TKI-related education, two follow-up telephone conversations, a printed information booklet and two adherence aids. Medication adherence (primary outcome), molecular responses and health-related quality of life (HRQoL) scores were assessed at baseline, 6th and 12th month. Medication adherence and HRQoL were assessed using medication possession ratio and the European Organisation for Research and Treatment in Cancer questionnaire (EORTC&#95;QLQ30&#95;CML24) respectively., Results: The MMS group (n = 65) showed significantly higher adherence to TKIs than the control group (n = 64) at 6th month (81.5% vs 56.3%; p = 0.002), but not at 12th month (72.6% vs 60.3%; p = 0.147). In addition, a significantly higher proportion of participants in the MMS group achieved major molecular response at 6th month (58.5% vs 35.9%; p = 0.010), but not at 12th month (66.2% vs 51.6%; p = 0.092). Significant deep molecular response was also obtained at 12th month (24.6% vs 10.9%; p = 0.042). Six out of 20 subscales of EORTC-QLQ30-CML24 were significantly better in the MMS group., Conclusions: The MMS improved CML patients' adherence to TKI as well as achieved better clinical outcomes., Trial Registration: Clinicaltrial.gov (ID: NCT03090477).

Background: Patient-reported outcome (PRO) measures developed and validated on patients with the currently defined phenotypes of chronic rhinosinusitis (CRS) are needed to support clinical trials in CRS., Objective: This study developed and examined the initial reliability and validity of the CRS-PRO, a new PRO measure of CRS., Methods: Instrument development was performed through structured interviews and focus groups with clinical experts and 45 patients with CRS meeting current definitions of disease, 21 patients with CRS without nasal polyps (CRSsNP), and 24 patients with CRS with nasal polyps (CRSwNP) to identify items important to patients. Then another 50 patients (32 with CRSsNP and 18 with CRSwNP) with stable CRS symptoms were enrolled to evaluate the reliability of the instrument. Each patient completed the CRS-PRO, Sinonasal Outcome Test-22 (SNOT-22), and 4 Patient-Reported Outcome Measurement Information System short forms at the baseline visit and then at least 7 days later., Results: After the development process, 21 items were identified from the conceptual domains of physical symptoms, sensory impairment, psychosocial effects, and life impact. Using the responses of the 50 patients with CRS, 21 draft items were further refined to 12 items by eliminating conceptually similar or highly correlated items or those with low mean symptom severity. The 12-item questionnaire was shown to have excellent internal consistency (Cronbach α, 0.86) and test-retest reliability with a high intraclass correlation coefficient (0.89) and Pearson's correlation (r = 0.82, P < .0001). The 12-item CRS-PRO correlated highly with the longer SNOT-22 (r = 0.83, P < .0001) demonstrating its concurrent validity. We also demonstrated validity and reliability in a separate analysis for patients with CRSsNP and CRSwNP., Conclusion: The CRS-PRO is a concise, valid, and reliable measure that was developed with extensive input from patients with CRS with current disease definitions., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The CRS-PRO is a new patient-reported outcome measure (PROM) for chronic rhinosinusitis (CRS) that was developed using extensive patient input per Food and Drug Administration guidance on PROMs acceptable for use as end points in clinical trials., Objective: To assess the responsiveness and convergent validity of the CRS-PRO following standard-of-care medical therapy., Methods: This was a prospective study of 51 patients (21 with nasal polyps and 30 without) with newly diagnosed CRS or having an acute CRS exacerbation who were initiated on appropriate medical therapy. At the baseline visit each patient completed the CRS-PRO questionnaire, the 22-item Sino-Nasal Outcome Test, the EuroQol 5-dimensional questionnaire, and 4 Patient-Reported Outcome Measure Information System short forms along with objective testing including endoscopic and radiographic scores, smell discrimination, and nasal inspiratory flow testing. This same battery of questionnaires and testing was administered at a follow-up visit 4 to 8 weeks later., Results: We verified that shortening the 21-item CRS-PRO to 12 items as previously described maintains its psychometric properties. The 12-item CRS-PRO was responsive with a large effect size (Cohen's d, 0.94) comparable to the longer 22-item Sino-Nasal Outcome Test (Cohen's d, 0.93). The instrument was slightly more responsive to medically treated patients with CRS without nasal polyps compared with patients with CRS with nasal polyps (Cohen's d, 1.1 vs 0.89, respectively). The change in 12-item CRS-PRO total score has moderate correlation with change in Lund-Mackay computed tomography scores., Conclusions: The CRS-PRO is a 12-item rigorously developed, responsive, and valid PROM that was developed using extensive input from patients with current definitions of CRS, including its 2 major phenotypes., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic rhinosinusitis (CRS) is a prevalent condition. Clinical diagnosis requires subjective evidence (i.e. symptoms) and objective evidence of inflammation (e.g. sinus computed tomography [CT]). Few studies have assessed differences in common CT scoring approaches for CRS, the Lund-Mackay (LM) system and its modified version (mLM); none in a general population sample. The aims of this study were to answer the following: (1) Is mLM superior to LM? (2) Should nasal cavity opacification be included in scoring? (3) How should location-specific scores be utilized? (4) If location-specific scores are summed, what should be the cutoff? (5) Are associations of opacification with symptoms observed when using different measurement approaches? We scored sinus CTs using LM and mLM from 526 subjects selected from a larger CRS study. Exploratory factor analysis (EFA) assessed similarity of mLM and LM. Latent class analysis (LCA) identified subgroups of sinus opacification patterns. Factors associated with group membership and relations with nasal and sinus symptoms (NSS) guided clinical relevance. EFA suggested no differences between LM and mLM, or after addition of nasal cavity opacification. LCA identified three opacification groups: no/mild, localized, and diffuse. Males were 2.7x more likely to have diffuse opacification than females, as were those with asthma or hay fever. A LM cutoff of 3 had similar performance to the currently used 4. Diffuse opacification was associated with nasal blockage and smell loss. Differing patterns of opacification may be clinically relevant, improving measurement of objective evidence in studies of CRS and sinus diseases., Competing Interests: The authors have declared that no competing interests exist.

Background: Chronic rhinosinusitis (CRS) is complicated by frequent acute exacerbations leading to significant health care burden and impaired quality of life., Objective: The objective of this study was to identify clinical factors associated with frequent acute exacerbation of CRS (AECRS)., Methods: This is a retrospective cohort study of patients with CRS from January 1, 2014, to May 31, 2016. Frequent AECRS was defined as at least 4 episodes over a 12-month period in which an antibiotic was prescribed for worsening sinus symptoms, and infrequent AECRS was defined as 0 to 3 episodes. Clinical factors, including asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease, were evaluated for associations between the 2 groups., Results: Of the 3109 patients with CRS who were identified, 600 (19.3%) were classified as having frequent exacerbation. Asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, and autoimmune disease were associated with frequent AECRS with statistically significant adjusted odds ratios (aORs) after controlling for age, race, and sex in multivariate analysis (asthma aOR = 2.61 [95% CI = 2.14-3.18]; allergic rhinitis aOR = 1.96 [95% CI = 1.58-2.42]; eosinophil count of at least 150 cells per microliter aOR = 1.54 [95% CI = 1.21-1.97]; and autoimmune disease aOR = 1.68 [95% CI = 1.36-2.07]). Antibody deficiency, antibiotic allergy, lower FEV 1 , radiographic sinus disease severity, nasal polyposis, and systemic corticosteroid use were also associated with frequent AECRS., Conclusion: Patients with frequent episodes of AECRS were characterized by a higher prevalence of asthma, allergic rhinitis, eosinophil count of at least 150 cells per microliter, autoimmune disease, and other allergic and immunologic diseases. These findings identify a high-risk phenotype of patients with CRS for preventive interventions to reduce exacerbation frequency., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a risk factor for dysglycemia, insulin resistance, and type 2 Diabetes Mellitus (T2DM). Inefficient energy oxidation, metabolic inflexibility, is a marker of blunted metabolism. We conducted a systematic review on metabolic inflexibility in women with PCOS. We searched MEDLINE, EMBASE and Cochrane central (inception-October 2018) for studies evaluating metabolic inflexibility and reporting on changes in Respiratory Quotient (ΔRQ). We extracted data and assessed quality using The Newcastle-Ottawa Scale. We included five prospective cohort studies (461 women). Three compared PCOS women to unaffected subjects, one to women with obesity or T2DM, and one to adolescent girls; all had medium quality. Three studies showed higher metabolic inflexibility in women with PCOS (ΔRQ range 0.05-0.098) compared to unaffected subjects. Women with PCOS had similar metabolic inflexibility compared to those with T2DM (ΔRQ 0.05 ± 0.03 vs 0.06 ± 0.04, p  = .98) and obesity ( p  = .06). Inflexibility was higher in hyperandrogenemic women with PCOS (ΔRQ 0.091 ± 0.060 vs 0.120 ± 0.010, p  = .014). ΔRQ was lower in PCOS women with insulin resistance vs those with normal insulin sensitivity (0.04 ± 0.02 vs. 0.07 ± 0.04, p  = .007). In conclusion, women with polycystic ovary syndrome appear to have higher metabolic inflexibility associated with hyperandrogenemia and insulin resistance.

Background: Invasive lobular carcinomas (ILC) form 5%-10% of breast cancer and rarely show overexpression of human epidermal growth factor receptor 2 ( HER2 )., Aim: To describe the prevalence and prognostic factors of HER2 positive ( HER2+ ) ILC in an Asian population., Methods: A retrospective review of patients with ILC seen between January 1985 and March 2018 at various SingHealth medical institutions was conducted. Demographic and clinical data were collected from medical records. We examined clinicopathological characteristics and survival in relation to HER2 status., Results: A total of 864 patients were included. Prevalence of HER2 positivity was 10.1% (87 patients). Compared with HER2 negative ( HER2- ) ILC, HER2+ ILC was associated with a higher proportion of estrogen receptor negative (24.4% vs 5.9%, P < 0.001), progesterone receptor negative ( PR- ) (40.2% vs 24%, P = 0.002) and grade 3 tumours (Grade 3, 29.0% vs 10.2%, P < 0.001). Overall survival rate was poorer in patients with HER2+ compared to HER2- ILC (56.7% vs 72.9% alive at 10 years; hazard ratio 1.87, 95% confidence interval: 1.21-2.90, P = 0.004). Based on multivariate analysis, negative prognostic factors for overall survival included HER2 positivity, PR negativity, older age, Indian ethnicity and higher tumour stage., Conclusion: Prevalence of HER2+ ILC was 10.1%. HER2+ ILC was more likely to have poorer prognostic features such as estrogen receptor negative, PR- and higher tumour grade, and have a poorer survival., Competing Interests: Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the removal of fractured instruments in mandibular incisor canals by using the trepan bur/microtube technique without a dental operating microscope (DOM)., Materials and Methods: Thirty-four mandibular incisors were selected, and 5-mm apical segments of #25/.06 taper K3 NiTi instruments were fractured in the apical portion of each canal. Coronal enlargement was performed, and a staging platform was prepared at the coronal aspect of the fractured instrument. Then, a trepan bur was used to expose 1-1.5 mm of the fragmented instrument, and a microtube device was used to withdraw the fragment. Microcomputed tomographic (micro-CT) imaging was used to evaluate the geometric changes in the root canal and dentin. The time required for fractured instrument removal in each sample was recorded, and the results were statistically analyzed with a paired t test., Results: The trepan bur/microtube technique exhibited a success rate of 76.47%, and the average fractured instrument removal time was 8.55 ± 5.81 min. The changes in canal volume and dentin volume from the coronal end of the fractured instrument to 1.5 mm apical to the end were significantly greater than those from the cementoenamel junction (CEJ) to the coronal end of the fractured instrument during fractured instrument removal (P < 0.0001)., Conclusions: The study showed that the trepan bur/microtube technique had a significant impact on geometric changes in the root canal and dentin from the coronal end of the fractured instrument to 1.5 mm apical to the end., Clinical Relevance: These findings suggest that the trepan bur/microtube technique may be an optional method for fractured instrument removal from relatively straight canals.

The development of biologics targeting various aspects of type 2 inflammation for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) will provide clinicians with powerful tools to help treat these patients. However, other therapies are also available, and positioning of biologics in a management algorithm will require comparative trials. In November 2019, the National Institute of Allergy and Infectious Diseases convened a workshop to consider potential future trial designs. Workshop participants represented a wide spectrum of clinical specialties, including otolaryngology, allergy, and pulmonary medicine, as well as expertise in CRSwNP pathophysiology and in trial methodology and statistics. The workshop discussed the current state of knowledge in CRSwNP and considered the advantages and disadvantages of various clinical trial or observational study designs and various clinical outcomes. The output from this workshop, which is presented in this report, will hopefully provide investigators with adequate information and ideas to design future studies and answer critical clinical questions. It will also help clinicians understand the current state of the management of CRSwNP and its gaps and be more able to interpret the new information to come., (Copyright © 2020. Published by Elsevier Inc.)

Background: Burned patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) have exceedingly high mortality rates of 73% to 100%. Since January 2011, we have been adopting an early RRT approach in managing burned patients with AKI. Our hypothesis was that early initiation of RRT leads to improved outcome and survival among burned patients with AKI., Methodology: We conducted a retrospective analysis of Burns Database in Singapore General Hospital from January 2011 to February 2016. Indications for dialysis included serum creatinine of greater than 1.5 times baseline or urine output of less than 0.5 mL/kg per hour for at least 6 consecutive hours. Patients with similar condition from January 2006 to December 2010 were recruited for comparison., Result: A total of 27 patients with burns and AKI were recruited from January 2011 to February 2016. The mean age was 45.4 years and 88.9% were male. The mean total burn surface area (TBSA) was 54.8%. The total volume of fluid resuscitation was 2.7 mL/kg per TBSA. The time from onset of burn to RRT was 6.4 days. Most patients presented with stage 1 AKI (51.9%), whereas 22.2% and 25.9% had stage 2 and stage 3 AKI, respectively. Most patients (74.1%) received CRRT and 18.5% received SLED. The mortality rate was 37.0% with majority of death (70%) due to sepsis/multiorgan failure. Only 1 patient required long-term RRT after discharge, and there was no occurrence of abdominal compartment syndrome. The mean age of 15 patients from 2006 to 2010 was 47.8 years. The mean TBSA was 49.5%. Only 26.7% of patients were started on RRT. The mortality rate was 66.7%, which was higher than that of subjects from 2011 to 2016 (37.0%) (P = 0.039)., Conclusions: Optimal timing of RRT for burned patients with AKI has not been established and data on early RRT approach are scarce. The findings of our study suggested that early RRT was associated with lower mortality rates among burned victims with AKI.

Background: Chronic rhinosinusitis (CRS) epidemiology has been largely studied using symptom-based case definitions, without assessment of objective sinus findings., Objective: To describe radiologic sinus opacification and the prevalence of CRS, defined by the co-occurrence of symptoms and sinus opacification, in a general population-based sample., Methods: We collected questionnaires and sinus CT scans from 646 participants selected from a source population of 200 769 primary care patients. Symptom status (CRS S ) was based on guideline criteria, and objective radiologic inflammation (CRS O ) was based on the Lund-Mackay (L-M) score using multiple L-M thresholds for positivity. Participants with symptoms and radiologic inflammation were classified as CRS S+O . We performed negative binomial regression to assess factors associated with L-M score and logistic regression to evaluate factors associated with CRS S+O . Using weighted analysis, we calculated estimates for the source population., Results: The proportion of women with L-M scores ≥ 3, 4, or 6 (CRS O ) was 11.1%, 9.9%, and 5.7%, respectively, and 16.1%, 14.6%, and 8.7% among men. The respective proportion with CRS S+O was 1.7%, 1.6%, and 0.45% among women and 8.8%, 7.5%, and 3.6% among men. Men had higher odds of CRS S+O compared to women. A greater proportion of men (vs women) had any opacification in the frontal, anterior ethmoid, and sphenoid sinuses., Conclusion: In a general population-based sample in Pennsylvania, sinus opacification was more common among men than in women and opacification occurred in different locations by sex. Male sex, migraine headache, and prior sinus surgery were associated with higher odds of CRS S+O ., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Lymphedema is the clinical manifestation of impaired lymphatic transport. It remains an under-recognized and under-documented clinical condition that still lacks a cure. Despite the substantial advances in the understanding of lymphatic vessel biology and function in the past two decades, there are still unsolved questions regarding the pathophysiology of lymphedema, especially in humans. As a consequence of impaired lymphatic drainage, proteins and lipids accumulate in the interstitial space, causing the regional tissue to undergo extensive and progressive architectural changes, including adipose tissue deposition and fibrosis. These changes are also associated with inflammation. However, the temporal sequence of these events, the relationship between these events, and their interplay during the progression are not clearly understood. Here, we review our current knowledge on the pathophysiology of lymphedema derived from human and animal studies. We also discuss the possible cellular and molecular mechanisms involved in adipose tissue and collagen accumulation during lymphedema. We suggest that more studies should be dedicated to enhancing our understanding of the human pathophysiology of lymphedema to pave the way for new diagnostic and therapeutic avenues for this condition., (Copyright © 2020 Azhar, Lim, Tan and Angeli.)

Introduction: Acute kidney injury (AKI) is a frequent complication of severe burn injury and is associated with a high mortality rate of up to 80%. We aimed to establish the incidence, mortality rate, and factors related to mortality in adult patients with severe burn injury and AKI with renal replacement therapy (RRT) in Singapore., Methods: We performed a retrospective cohort study of severely burned patients who were admitted to the Burns Intensive Care Unit (BICU) at the Singapore General Hospital (SGH) from January 2008 to December 2016. We compared patients with AKI with RRT who survived with those who did not survive. As there were changes in the protocol for burns management after 2013, we also compared patients with AKI with RRT who survived with non-survivors in each of the 2008-2012 and 2013-2016 cohorts., Results: Data of 201 patients were studied. The incidence of AKI with RRT use in severe burn injury was 21.9% and their mortality rate was 50.0%. The non-survivors had significantly higher median burned total body surface area (p = 0.043), earlier AKI (p = 0.046), earlier use of RRT (p = 0.035), lower rate of renal recovery (p = <0.0001), higher rates of adult respiratory distress syndrome (ARDS) (p = 0.005) and shock with vasopressors (p = 0.009) compared to the survivors. The survival rate was 36.8% in the 2008-2012 cohort, but improved to 60.0% in the 2013-2016 cohort. In the 2008-2012 cohort, the non-survivors developed AKI earlier (day 0 admission vs. day 3 admission, p = 0.039), and were initiated on RRT at lower serum creatinine level (173.5 μmol/L vs. 254.0 μmol/L, p = 0.042), when compared to the survivors in this same cohort. On the other hand, there were no significant differences in the renal status and fluid balance parameters between the non-survivors and survivors in the 2013-2016 cohort., Conclusions: The incidence of AKI with RRT in the Singapore study cohort was high, but their mortality rate was relatively lower compared to other study cohorts. Severity of AKI and use of RRT were associated with poor prognosis. Large scale study is required to further study the risk factors for mortality in this group of patients and establish cause-and-effect relationship., (Copyright © 2019 Elsevier Ltd and ISBI. All rights reserved.)

Objective: To assess the health utility of chronic Eustachian tube dysfunction (ETD)., Methods: This is a prospective study of 53 patients with chronic ETD recruited from a tertiary clinic from April 2017 to July 2018. The 7-Item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) was administered, and health utility was evaluated using the EuroQol-5 Dimensions-3 Level Instrument (EQ-5D-3L), the visual analogue scale (VAS), time tradeoff (TTO), and standard gamble (SG). Participants were grouped into medical or procedural management groups. One-week follow-up included repeated health utility measures and ETDQ-7., Results: Fifty-three patients were included in the final analysis. Of those, 34 were managed medically, and 19 received myringotomies ± PE tubes. The mean baseline ETDQ-7 was 4.26 ± 1.31; whereas health utility measures were different depending on the method utilized: EQ-5D-3L 0.90 ± 0.11; VAS 0.76 ± 0.21; TTO 0.85 ± 0.23; and SG 0.94 ± 0.11 (P < .001). There was a significant change in ETDQ-7 (P = .001) and TTO (P = .011) scores posttreatment. On the ETDQ-7, question 2 (pain in the ears) was significantly associated with VAS (P = .032), and question 4 (ear symptoms during a cold or sinusitis) was significantly associated with TTO (P = .006)., Conclusion: Chronic ETD has a significant burden on quality of life, with a health utility similar to gastroesophageal reflux disease and moderate asthma. Although treatment-related changes are measurable using disease-specific quality-of-life measures, only TTO was significantly changed after treatment. Health utility seemed to depend on the method of measurement but provided a benchmark for evaluating cost-effectiveness of innovations to manage ETD., Level of Evidence: 2 Laryngoscope, 130:E39-E44, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Numerous advancements have been made in the surgical treatment of gynecomastia. However, one of the greatest challenges faced is the complete excision of the fibrous breast disc. We aim to review and compare the outcomes of the microdebrider excision and liposuction technique (MELT) with other techniques employed at our institution., Methodology: We reviewed patients who underwent treatment for idiopathic gynecomastia at our institution from 2002 to 2017. They were divided into 4 groups: Microdebrider Excision and Liposuction Technique (MELT), liposuction only (LO), open excision only (EO), and liposuction and open excision technique (LET). Complications requiring a revision surgery were recorded (residual breast disc, hematoma formation, and nipple-areolar scars). Phone interviews were conducted to evaluate patient satisfaction., Results: A total of 304 patients underwent treatment between 2002 and 2017. Out of which, 51.3% patients were treated by MELT, 17.1% patients by LO, 15.8% patients by EO, and 15.8% patients by LET. The subgroup analysis on patients with clinically palpable breast disc was performed. Patients who underwent LO were 2.58 times more likely to have a revision surgery (p = 0.030) and 4.05 times more likely to have residual breast disc requiring revision surgery (p = 0.006) compared to the MELT group. Patients who underwent LET were 3.26 times more likely to have hematomas compared to the MELT group (p = 0.047). Patients from the EO group were most concerned by scars (p = 0.003)., Conclusion: The MELT is a useful technique for the treatment of gynecomastia especially for patients with palpable breast discs. It can achieve good clinical and satisfaction outcomes as compared to other traditional techniques via a small single incision., Competing Interests: Declaration of Competing Interest The authors do not have any conflict of interest or funding to declare., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background:  Trachea reconstruction requires creation of a functional lining, semirigid support, and vascularity. We aimed to design composite flaps with these three components in a rabbit model., Methods:  Circumferential ( n  = 9) and partial anterior ( n  = 8) tracheal defects were created in rabbits. A circumferential defect was reconstructed with a tubed ear flap incorporating cartilage for support and skin for lining. This was pedicled on the posterior auricular vessels and tunneled into the neck to bridge the defect. In the second experiment, a longitudinal anterior trachea defect was patched with a pedicled rib cartilage and intercostal muscle flap based on the internal mammary vessels. The vascularized fascia over the intercostal muscles replaced the lining while the cartilage provided support. Postoperatively, the rabbits were monitored clinically and endoscopically. The tracheal constructs were examined histologically after the animals were sacrificed., Results:  Rabbits with circumferential defects reconstructed with the ear flap survived up to 6 months. Histology demonstrated vascularized cartilage with good integration of the flap with native trachea. However, hair growth and skin desquamation resulted in airway obstruction in the long term. In the second experiment, all the rabbits survived without respiratory distress, and the intercostal muscle fascia was completely covered by native respiratory epithelium., Conclusion:  We described two experimental techniques using autologous composite flaps for single-stage trachea reconstruction in a rabbit model. Skin was a poor lining replacement, whereas vascularized muscle fascia became covered with respiratory epithelium. A rib cartilage and muscle flap could potentially be used for reconstruction of partial defects in humans., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To identify the role of Staphylococcus aureus (SA) or its intracellular small-colony variant phenotype (SCV) with co-trimoxazole (CTX) or ANCA-associated vasculitis (AAV) activity., Methods: All consecutive AAV patients with granulomatosis with polyangiitis (GPA), eosinophilic GPA or microscopic polyangiitis, followed at the French National Vasculitis Referral Center (09/2012-05/2013), and hospitalized non-AAV controls, exclusively for SA/SCV carriage comparisons, were enrolled. All had bilateral anterior nasal swab cultures. Nasal SA or SCV carriage was determined and associations with relapse(s), BVAS, ANCA-positivity, anti-staphylococcal and immunosuppressant use, were analysed ⩾4 years post-inclusion., Results: Nasal SA carriage rates did not differ among AAVs (P = 0.53): GPA (24/80; 30%), EGPA (7/28; 25%) and microscopic polyangiitis (3/11; 27.3%); and the rate was less frequent in controls than in GPA patients not taking CTX (P = 0.04). AAV patients taking CTX prophylaxis had less nasal SA carriage (8.7% vs 36.2%; P = 0.02). Nasal SA carriage or CTX use did not modify relapse rates, BVAS or ANCA-positivity at inclusion or during follow-up. Nasal SCV carriage, found in 15/207 (7.2%) patients, was similar for GPA (10/24; 41.7%), microscopic polyangiitis (2/7; 28.6%) and eosinophilic GPA (2/3; 66.7%), but higher (P = 0.02) than controls (1/14; 7.1%). SCV carriage by AAV groups did not modify relapse rates or ANCA positivity at inclusion or during follow-up; a trend towards higher BVAS was observed only for anti-PR3 ANCA patients., Conclusion: Nasal SA or SCV carriage was comparable among AAVs but more frequent than in controls. Nasal SA or SCV carriage and CTX use did not modify AAV relapse rates., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of activated group 2 innate lymphoid cells (ILC2s) and elevation of thymic stromal lymphopoietin (TSLP). A member of the TNF superfamily (TNFSF), TNFSF15, is known to induce the production of type 2 cytokines in ILC2s. Although ILC2s have been implicated in CRSwNP, the presence and role of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP has not been elucidated. Here, we investigate the involvement of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP. We found that receptor activator of NF-κB (RANK) ligand (RANK-L (TNFSF11)) was significantly elevated in nasal polyps (NPs), and that the receptor of RANK-L, RANK, was expressed on ILC2s in human peripheral blood and NPs. An agonistic antibody against RANK induced production of type 2 cytokines in human ILC2s, and TSLP significantly enhanced this reaction. The membrane-bound RANK-L was detected mainly on CD45 + immune cells, including T H 2 cells in NPs. The co-culture of NP-derived ILC2s and T H 2 cells significantly enhanced production of type 2 cytokines, and anti-RANK-L monoclonal antibody suppressed this enhancement. In conclusion, RANK-L, together with TSLP, may play an inductive role in the ILC2-mediated type 2 inflammation in CRSwNP.

Background: Chronic rhinosinusitis (CRS) is associated with bronchiectasis; however, this relationship has not been well studied in the United States (US) population. In this work we aimed to determine the prevalence of CRS among patients with bronchiectasis affiliated with a US tertiary medical center and identify which comorbid diseases are associated with the presence of CRS in patients with bronchiectasis., Methods: This was a retrospective cohort study in which data were obtained from a large database warehouse at a tertiary care center. Patients with bronchiectasis were identified from 2007 to 2017 using diagnosis codes from the the ninth and tenth revisions of the International Classification of Diseases (ICD-9/10) and confirmed by radiographic evidence of bronchiectasis on chest computed tomography (CT) scans. Patients were divided into cohorts based on presence or absence of concomitant CRS. Characteristics analyzed included demographics, comorbidities, peripheral eosinophil counts, and pulmonary function testing., Results: CRS was present in 45% (408 of 900) of patients with bronchiectasis. Females represented a majority of bronchiectasis patients, both with and without CRS (69% and 64%, respectively, p = 0.09). After controlling for demographic factors, asthma (p < 0.01), allergic rhinitis (p < 0.01), gastroesophageal reflux disease (p < 0.01), and antibody deficiency (p < 0.01) were associated with the presence of CRS in patients with bronchiectasis., Conclusion: CRS had a high prevalence and was associated with numerous comorbid conditions in patients with bronchiectasis. These findings have clinical implications for the treatment of patients with bronchiectasis and future research., (© 2019 ARS-AAOA, LLC.)

Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease subdivided based on the presence or absence of nasal polyps (NPs). Histologic features of chronic rhinosinusitis with nasal polyps (CRSwNP) include inflammatory cell infiltration and excessive fibrin deposition in NPs. Thrombin-activatable fibrinolysis inhibitor (TAFI) is an enzyme that plays an antifibrinolytic role in the body. The significance of TAFI has been documented in patients with chronic inflammatory diseases, including chronic lung disease; however, it has not been evaluated in the pathogenesis of NPs., Objective: The objective of this study was to evaluate the potential role of TAFI in the pathogenesis of NPs., Methods: Nasal lavage fluid was collected from control subjects and patients with CRS. We measured levels of thrombin/anti-thrombin complex (TATc) and TAFI protein using an ELISA., Results: TATc levels in nasal lavage fluid were significantly increased in patients with CRSwNP and patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with control subjects, and TAFI levels in nasal lavage fluid were also significantly increased in patients with CRSwNP compared with those in control subjects and patients with CRSsNP. There was a significant correlation between TATc and TAFI levels in nasal lavage fluid. Interestingly, patients with CRS and asthma showed increased TATc and TAFI levels in nasal lavage fluid compared with those in patients with CRS without asthma, especially patients with CRSwNP., Conclusions: Increased TATc and TAFI levels in nasal passages of patients with CRSwNP might participate in fibrin deposition in NPs and might play a role in the pathogenesis of CRSwNP and asthma., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Coronary heart disease is rapidly increasing in developing countries, but access to cardiac rehabilitation and secondary prevention remains low. In this study, we aimed to assess the effectiveness of a smartphone-based cardiac rehabilitation and secondary prevention programme delivered via the social media platform WeChat (SMART-CR/SP)., Methods: In this parallel-group, single-blind, randomised controlled trial, we recruited patients aged 18 years or older with coronary heart disease who had received percutaneous coronary interventions from a large tertiary hospital in Shanghai, China. Participants were randomly assigned (1:1) by block randomisation to either a 2-month intensive programme followed by a 4-month step-down phase of SMART-CR/SP or to usual care. In the SMART-CR/SP group, participants received comprehensive cardiac rehabilitation and secondary prevention via WeChat. The usual care group received standard outpatient cardiology follow-up but without formal cardiac rehabilitation and secondary prevention. Assessments were done at baseline, 2 months, 6 months, and 12 months. The primary outcome was change in functional capacity from baseline, measured by 6-min walk distance, at 2 months and 6 months. Analysis was by intention to treat. Research personnel involved in assessments were blinded to group allocation. Adverse-event analysis was based on percentage of patients who discontinued the study owing to adverse events. SMART-CR/SP programme-related safety issues were also recorded. This study was registered with the Chinese Clinical Trial Registry, number ChiCTR-INR-16009598., Findings: Between Nov 17, 2016, and March 18, 2017, 312 patients (mean age 60·5 years [SD 9·2]), of whom 58 (19%) were female and 254 (81%) were male, were recruited and subsequently randomly assigned to SMART-CR/SP (n=156) or usual care (n=156). The improvement in 6-min walk distance at 2 months was significantly greater in the SMART-CR/SP group (from 489·2 m [99·4] at baseline to 539·1 m [68·0]) than in the control group (from 485·0 m [93·5] at baseline to 517·8 m [74.6]), with an adjusted mean difference of 20·64 m (95% CI 7·50-33·77; p=0·034). This improvement was maintained at 6 months (mean 6-min walk distance 543·4 m [67·5] in the SMART-CR/SP group vs 523·5 m [60·2] in the control group), with a mean between-group difference of 22·29 m (8·19-36·38; p=0·027). No adverse events or SMART-CR/SP programme-related safety issues were reported by participants during the study., Interpretation: SMART-CR/SP was found to be a cardiac rehabilitation and secondary prevention service model with high efficacy and accessibility and to be easy to use. These results justify the implementation of similar models of care on a broader scale., Funding: Curtin University., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation in the nose and paranasal sinuses. Inflammation in CRS is also heterogeneous and is mainly characterized by type 2 (T2) inflammation, but subsets of patients show type 1 (T1) and type 3 (T3) inflammation. Whether inflammatory endotypes are associated with clinical phenotypes has yet to be explored in detail., Objective: To identify associations between inflammatory endotypes and clinical presentations in CRS., Methods: We compared 121 patients with nonpolypoid CRS (CRSsNP) and 134 patients with polypoid CRS (CRSwNP) and identified inflammatory endotypes using markers including IFN-γ (T1), eosinophil cationic protein (T2), Charcot-Leyden crystal galectin (T2), and IL-17A (T3). We collected clinical parameters from medical and surgical records and examined whether there were any associations between endotype and clinical features., Results: The presence of nasal polyps, asthma comorbidity, smell loss, and allergic mucin was significantly associated with the presence of T2 endotype in all patients with CRS. The T1 endotype was significantly more common in females, and the presence of pus was significantly associated with T3 endotype in all patients with CRS. We further analyzed these associations in CRSsNP and CRSwNP separately and found that smell loss was still associated with T2 endotype and pus with the T3 endotype in both CRSsNP and CRSwNP. Importantly, patients with CRS with T2 and T3 mixed endotype tended to have clinical presentations shared by both T2 and T3 endotypes., Conclusions: Clinical presentations are directly associated with inflammatory endotypes in CRS. Identification of inflammatory endotypes may allow for more precise and personalized medical treatments in CRS., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)