Attosecond field emission.

Field emission of electrons underlies great advances in science and technology, ranging from signal processing at ever higher frequencies1 to imaging of the atomic-scale structure of matter2 with picometre resolution. The advancing of electron microscopy techniques to enable the complete visualization of matter on the native spatial (picometre) and temporal (attosecond) scales of electron dynamics calls for techniques that can confine and examine the field emission on sub-femtosecond time intervals. Intense laser pulses have paved the way to this end3,4 by demonstrating femtosecond confinement5,6 and sub-optical cycle control7,8 of the optical field emission9 from nanostructured metals. Yet the measurement of attosecond electron pulses has remained elusive. We used intense, sub-cycle light transients to induce optical field emission of electron pulses from tungsten nanotips and a weak replica of the same transient to directly investigate the emission dynamics in real time. Access to the temporal properties of the electron pulses rescattering off the tip surface, including the duration τ = (53 as ± 5 as) and chirp, and the direct exploration of nanoscale near fields open new prospects for research and applications at the interface of attosecond physics and nano-optics.

Laser picoscopy of valence electrons in solids.

Valence electrons contribute a small fraction of the total electron density of materials, but they determine their essential chemical, electronic and optical properties. Strong laser fields can probe electrons in valence orbitals1-3 and their dynamics4-6 in the gas phase. Previous laser studies of solids have associated high-harmonic emission7-12 with the spatial arrangement of atoms in the crystal lattice13,14 and have used terahertz fields to probe interatomic potential forces15. Yet the direct, picometre-scale imaging of valence electrons in solids has remained challenging. Here we show that intense optical fields interacting with crystalline solids could enable the imaging of valence electrons at the picometre scale. An intense laser field with a strength that is comparable to the fields keeping the valence electrons bound in crystals can induce quasi-free electron motion. The harmonics of the laser field emerging from the nonlinear scattering of the valence electrons by the crystal potential contain the critical information that enables picometre-scale, real-space mapping of the valence electron structure. We used high harmonics to reconstruct images of the valence potential and electron density in crystalline magnesium fluoride and calcium fluoride with a spatial resolution of about 26 picometres. Picometre-scale imaging of valence electrons could enable direct probing of the chemical, electronic, optical and topological properties of materials.

Biomechanical comparison of bone staple fixation methods with suture material for median sternotomy closure using 3D-printed bone models.

AIM: To compare the biomechanical properties of three different sternal closure techniques in a 3D-printed bone model of a sternum from a 30-kg dog. METHODS: Median sternotomy was performed on a total of 90 three-dimensional (3D) copies of a polycarbonate (PC) model of a sternum, generated from the CT images of the sternum of a 30-kg German Shepherd dog. Three different methods were used to repair the sternotomies: polydioxanone suture (group PDS, n = 30), stainless steel bone staples (group SS, n = 30), and nitinol bone staples (group NS, n = 30). Each repair method was tested by applying tensile force in one of three ways (longitudinally, laterally, or torsionally) resulting in a sample size of n = 10 for each repair method-loading combination. In all experiments, the loads at 1-mm and 2-mm gap formation, failure, and the displacement at the failure point were measured. RESULTS: In lateral distraction and longitudinal shear tests, NS and SS staple repairs required application of significantly greater force than PDS across all displacement criteria (1 and 2 mm). NS exhibited significantly greater failure load than PDS. In torsion tests, NS required significantly greater application of force compared to SS or PDS at all displacement criteria (1 and 2 mm) and exhibited a greater failure load than PDS. In terms of displacement at failure point, PDS suture showed more displacement than SS or NS across all experiments (laterally, longitudinally, torsionally). CONCLUSIONS: In this study, bone staples were mechanically superior to PDS suture in median sternotomy closure using 3D-printed bone model in terms of 1-mm, 2-mm displacement loads, and displacement at failure. NS had a higher failure load than PDS under lateral, longitudinal, and torsional distraction. CLINICAL RELEVANCE: These study results imply that bone staples can be considered as an alternative surgical method for median sternotomy closure in dogs.

Petahertz-scale spectral broadening and few-cycle compression of Yb:KGW laser pulses in a pressurized, gas-filled hollow-core fiber.

We demonstrate efficient generation of coherent super-octave pulses via a single-stage spectral broadening of a Yb:KGW laser in a single, pressurized, Ne-filled, hollow-core fiber capillary. Emerging pulses spectrally spanning over more than 1 PHz (250-1600 nm) at a dynamic range of ∼60 dB, and an excellent beam quality open the door to combining Yb:KGW lasers with modern light-field synthesis techniques. Compression of a fraction of the generated supercontinuum to intense (8 fs, ∼2.4 cycle, ∼650 µJ) pulses allows convenient use of these novel laser sources in strong-field physics and attosecond science.

Short-term neonatal and long-term infant outcome of late-preterm twins: nationwide population-based study.

OBJECTIVES: To evaluate the short- and long-term outcome of late-preterm compared with term birth in twin pregnancy. METHODS: This retrospective observational cohort study included all women who had a twin delivery between 1 January 2007 and 31 December 2010 recorded in the claims database of the Korea National Health Insurance, with at least one follow-up recorded in the database of the National Health Screening Program for Infants and Children. Outcomes were analyzed at the pregnancy level, with adverse outcome being defined as an adverse outcome in one or both twins, identified by a diagnosis according to the International Classification of Diseases 10th Revision. The primary short-term outcome was composite morbidity, which included any of the following: transient tachypnea, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage and bronchopulmonary dysplasia. Long-term adverse outcome included any neurological or neurodevelopmental outcome, defined by prespecified neurological and developmental diagnoses; these were assessed by following up all neonates until the end of 2018, by which time they were 8-11 years of age. Outcomes were compared between twins delivered late preterm (34 + 0 to 36 + 6 weeks) and those delivered at term (≥ 37 weeks). RESULTS: Among 17 189 women who delivered twins at ≥ 34 weeks of gestation during the study period, 5032 (29.27%) women delivered in the late-preterm period. On multivariate analysis, compared with the twins delivered at term, the late-preterm twins had an increased risk for the primary short-term outcome of composite morbidity (adjusted odds ratio (aOR), 2.09; 95% CI, 1.90-2.30), including transient tachypnea (aOR, 1.85; 95% CI, 1.64-2.09), respiratory distress syndrome (aOR, 2.31; 95% CI, 2.04-2.62), necrotizing enterocolitis (aOR, 2.10; 95% CI, 1.20-3.69) and intraventricular hemorrhage (aOR, 2.13; 95% CI, 1.46-3.11). For the long-term outcome, the late-preterm twins also had an increased risk for any neurological or neurodevelopmental outcome (adjusted hazard ratio, 1.14; 95% CI, 1.07-1.21). CONCLUSIONS: Twins delivered in the late-preterm period have an increased risk for short- and long-term morbidity compared with twins delivered at term. These results should be considered when determining the timing of delivery in uncomplicated twin pregnancy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Incidence of subsequent osteoporotic fractures after distal radius fractures and mortality of the subsequent distal radius fractures: a retrospective analysis of claims data of the Korea National Health Insurance Service.

A better understanding of the features of subsequent fractures after distal radius fracture (DRF) is important for the prevention of further osteoporotic fractures. This study found that the cumulative incidence of subsequent osteoporotic fractures in South Korea increased over time and that the mortality rates of subsequent DRFs were lower than those of first-time DRFs. INTRODUCTION: We examined the incidence of osteoporotic fractures following distal radius fractures (DRFs) and the mortality rate after subsequent DRFs using claims data from the Korea National Health Insurance (KNHI) Service. METHODS: We identified records for 41,417 patients with first-time DRFs in 2012. The occurrence of osteoporotic fractures of the spine, hip, wrist, and humerus at least 6 months after the index DRF was tracked through 2016. All fractures were identified by specific diagnosis and procedure codes. One-year mortality rates and standardized mortality ratios (SMRs) for initial and subsequent DRFs were calculated for all patients. RESULTS: The 4-year cumulative incidence of all subsequent osteoporotic fractures was 14.74% (6105/41,417; 9.47% in men, 15.9% in women). The number of associated subsequent fractures was 2850 for the spine (46.68%), 2271 for the wrist (37.2%), 708 for the hip (11.6%), and 276 for the humerus (4.52%). The cumulative mortality rate 1 year after the first-time and subsequent DRF was 1.47% and 0.71%, respectively, and the overall SMR was 1.48 (95% CI: 1.37-1.61) and 0.71 (95% CI: 0.42-1.21), respectively. CONCLUSION: The cumulative incidence of osteoporotic fractures following DRFs increased over the study period and was higher among women. The cumulative mortality rates and SMRs of subsequent DRFs were lower than those of first-time DRFs at the 1-year follow-up. Given the increasing incidence rate of DRFs, the incidence of subsequent osteoporotic fractures may also increase.

Postpartum haemorrhage requiring transfusion and risk of cardiovascular disease later in life: a retrospective cohort study.

OBJECTIVE: To determine whether postpartum haemorrhage (PPH) is associated with cardiovascular disease (CVD), including cerebrovascular and ischaemic heart disease beyond the peripartum period. DESIGN: Population-based cohort study. SETTING: Merged databases of the Korea National Health Insurance (KNHI) claims, National Health Screening Examination and National Health Screening Program for Infants and Children. POPULATION: Women who gave birth in 2007 in the Republic of Korea and who were tracked through to 2015 for the occurrence of CVD. METHODS: Patients were identified and the occurrences of PPH and transfusion were determined using the KNHI claims database. The occurrence of CVD was tracked through 2015 using codes from the International Classification of Diseases, tenth revision (ICD-10). MAIN OUTCOME MEASURES: The risk of CVD after PPH. RESULTS: Among 150 381 women who gave birth during the study period, 9107 were diagnosed with PPH and 899 were treated with transfusion. The risk of CVD in women with PPH was no different than in women without PPH, after adjustment (HR 1.03, 95% CI 0.93-1.13). The risk of CVD in women with PPH requiring transfusion was significantly increased compared with women without PPH, after adjustment (HR 1.60, 95% CI 1.25-2.06). The risk of CVD in women with PPH without transfusion was not significantly different compared with women without PPH (HR 0.96, 95% CI 0.86-1.07). CONCLUSIONS: Postpartum haemorrhage (PPH) requiring transfusion is associated with an increased risk of CVD. Guidelines for management should be established, and further studies on the mechanisms involved should be conducted. TWEETABLE ABSTRACT: PPH requiring transfusion is associated with an increased risk of CVD.

Antimicrobial effects of three herbs (Brassica juncea, Forsythia suspensa, and Inula britannica) on membrane permeability and apoptosis in Salmonella.

AIMS: This study aimed synergistic effects of three herbs in Salmonella via increased membrane permeability and apoptosis. METHODS AND RESULTS: Using high-performance liquid chromatography, four types of phenylethyl glycosides and a lignan were detected in the herb mixture (Brassica juncea, Forsythia suspensa, and Inula britannica). During treatment with the herb mixture (1×, 2×, or 4× the MIC), viable cells decreased to 1·87 log CFU per ml (Salmonella Gallinarum) and 2·33 log CFU per ml (Salmonella Enteritidis) after 12 h of incubation according to inhibition of tricarboxylic acid cycle (P < 0·01). In addition, N-phenyl-1-naphthylamine uptake increased from 229·00 to 249·67 AU in S. Gallinarum and from 232·00 to 250·67 AU in S. Enteritidis (P < 0·05), whereas membrane potential decreased from 8855·00 to 3763·25 AU and from 8703·67 to 4300·38 AU, respectively. Apoptotic Salmonella cells were observed by confocal laser scanning microscopy and flow cytometry. Transmission electron microscopy observations with negative staining showed protein leakage from damaged Salmonella. CONCLUSIONS: These results showed the synergistic effect of the three herbs against avian pathogenic Salmonella induced by membrane damage and apoptosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Salmonella causes enormous economic losses in the poultry industry. These results indicated that potency of natural antimicrobial agents due to apoptosis in Salmonella.

Thyroid surgery during coronavirus-19 pandemic phases I, II and III: lessons learned in China, South Korea, Iran and Italy.

OBJECTIVE: We compared demographic and clinic-pathological variables related to the number of surgeries for thyroid conditions or for cancer, morbidity, and fine needle aspiration (FNA) practices among Covid19 pandemic phases I, II, III and the same seasonal periods in 2019. METHODS: The prospective database of the Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, China was used for this study. Covid19 emergency levels were stratified according to the World Health Organization: phase I (January 25-February 25, 2020), phase II (February 26-March 19), phase III (March 20-April 20). RESULTS: There were fewer outpatient FNAs and surgeries in 2020 than in 2019. There were no thyroid surgeries during phase I. There were also fewer surgeries for cancer with a significant reduction of advanced stage cancer treatments, mainly stage T1b N1a in phase II and T3bN1b in phase III. Operative times and postoperative stays were significantly shorter during the pandemic compared to our institutional baseline. In phase III, vocal cord paralysis (VCP) increased to 4.3% of our baseline numbers (P = 0.001). There were no cases of Covid19-related complications during the perioperative period. No patients required re-admission to the hospital. CONCLUSION: The Covid19 outbreak reduced thyroid surgery patient volumes. The decrease of Covid19 emergency plans contributed to unexpected outcomes (reduction of early stage cancer treatment, decreased operative times and hospital stays, increased VCP rate).

STIM1 knock-down decreases the affinity of obinutuzumab for CD20 by altering CD20 localization to Triton-soluble membrane.

Obinutuzumab is thought to exert its effects through its high antibody-dependent cellular cytotoxicity (ADCC) via glyco-engineering of the Fc region. In addition, obinutuzumab causes direct binding-induced cell death (DCD) only by specifically binding to its target CD20, a Ca2+ channel. However, the specific features of CD20 related to obinutuzumab binding-induction of cell death are not clearly understood. In this study, we evaluated the relationship between the Ca2+ channel features of CD20 as a store-operated Ca2+ channel (SOC) and obinutuzumab binding-induced cell death. Ca2+ channel function and biochemical analysis revealed that CD20 is an Orai1- and stromal interaction molecule (STIM1)-dependent Ca2+ pore. However, binding of obinutuzumab on CD20 did not have any effect on Ca2+ influx activity of CD20; the direct cell death rate mediated by obinutuzumab binding was almost equivalent with or without the extracellular Ca2+ condition. Given the apparent interaction between STIM1 and CD20, we observed Triton-X solubilized obinutuzumab-bound CD20 accompanied by STIM1. Subsequently, obinutuzumab binding and cell death were decreased by STIM1 knock-down in Ramos B cells. Thus, STIM1 directly contributes to cell death by increasing the affinity of cells for obinutuzumab by transferring CD20 to the Triton-soluble membrane region.

Exploring Relative Preferences for HIV Service Features Using Discrete Choice Experiments: a Synthetic Review.

PURPOSE OF REVIEW: Aligning HIV treatment services with patient preferences can promote long-term engagement. A rising number of studies solicit such preferences using discrete choice experiments, but have not been systematically reviewed to seek generalizable insights. Using a systematic search, we identified eleven choice experiments evaluating preferences for HIV treatment services published between 2004 and 2020. RECENT FINDINGS: Across settings, the strongest preference was for nice, patient-centered providers, for which participants were willing to trade considerable amounts of time, money, and travel distance. In low- and middle-income countries, participants also preferred collecting antiretroviral therapy (ART) less frequently than 1 monthly, but showed no strong preference for 3-compared with 6-month refill frequency. Facility waiting times and travel distances were also important but were frequently outranked by stronger preferences. Health facility-based services were preferred to community- or home-based services, but this preference varied by setting. In high-income countries, the availability of unscheduled appointments was highly valued. Stigma was rarely explored and costs were a ubiquitous driver of preferences. While present improvement efforts have focused on designs to enhance access (reduced waiting time, travel distance, and ART refill frequency), few initiatives focus on the patient-provider interaction, which represents a promising critical area for inquiry and investment. If HIV programs hope to truly deliver patient-centered care, they will need to incorporate patient preferences into service delivery strategies. Discrete choice experiments can not only inform such strategies but also contribute to prioritization efforts for policy-making decisions.

Differentiation of dural arteriovenous fistula from reflux venous flow on 3D TOF-MR angiography: identifying asymmetric enlargement of external carotid artery branches.

AIM: To differentiate dural arteriovenous fistula (DAVF) from reflux venous flow (RVF) by assessment of asymmetric enlargement of external carotid artery (ECA) branches on three-dimensional (3D) time-of-flight magnetic resonance angiography (TOF-MRA). MATERIALS AND METHODS: Nineteen patients with DAVF and 27 patients with RVF were included from September 2007 to April 2019. The locations of DAVF were the cavernous (n=9) and sigmoid-transverse (n=6) sinuses, and the jugular (n=3) and sphenoparietal (n=1) veins. Two radiologists visually assessed asymmetric enlargement of the ascending pharyngeal artery (ASP), middle meningeal artery (MMA), accessory meningeal artery (AMA), artery of the foramen rotundum, and occipital artery. MMA size was also measured quantitatively. RESULTS: More frequent asymmetric enlargement of the ASP and MMA were seen in DAVF than in RVF (17 of 19 versus 3 of 27 for ASP; 16 of 19 versus 1 of 27 for MMA, p<0.01). The AMA, artery of the foramen rotundum, and occipital arteries were not visualised in RVF patients. The ipsilateral MMA size was significantly larger in DAVF than in RVF (2.14 versus 0.64 mm2, p< 0.01). The diagnostic performance of ipsilateral MMA size for DAVF was good, with an area under the receiver operating characteristic curve of 0.89, with a sensitivity of 84.2% and a specificity of 81.5% at a cut-off of 1.08 mm2. CONCLUSIONS: DAVF showed significantly larger ECA branches than RVF on 3D TOF-MRA. Therefore, thorough evaluation of ECA branches could help to differentiate DAVF from RVF.

Extended approach or usage of nasoseptal flap is a risk factor for olfactory dysfunction after endoscopic anterior skullbase surgery: results from 928 patients in a single tertiary center.

BACKGROUND: The aim of this study was to compare olfactory function change in patients who underwent endoscopic skull-base surgery. METHODOLOGY: A total of 928 patients were included in this retrospective study. Olfactory function was measured using the non- validated Likert scale (0â€"100), the Cross-Cultural Smell Identification Test (CC-SIT) and the butanol threshold test (BTT). Patients were divided into two groups: an endoscopic trans-sellar approach group (ETA, n = 768) and an extended endoscopic endonasal approach group (EEEA, n = 160). The ETA group was sub-divided into Nasoseptal flap (NSF) and no NSF groups. RESULTS: Non-validated olfactory function significantly worsened in the EEEA and ETA-NSF groups compared with that in the ETA- no NSF group for at least 6 months post-operatively. Validated olfactory impairment (BTT and CC-SIT) was also significantly worse in the EEEA and NSF groups compared with that in the ETA-no NSF group 3 months post-operatively. Additionally, the degrees of non-validated and validated olfactory deterioration were not significantly different between the EEEA and ETA-NSF groups. We also found that CC-SIT score changes were significantly impaired in tuberculum sellae meningioma patients than in craniopharyn- gioma patients. CONCLUSIONS: We conclude that NSF was the key factor that led to olfactory impairment after endoscopic skull-base surgery.

Women with threatened preterm labour followed by term delivery have an increased risk of spontaneous preterm birth in subsequent pregnancies: a population-based cohort study.

OBJECTIVES: To evaluate the association of a history of threatened preterm labour (TPL) followed by term delivery with the risk of spontaneous preterm delivery (PTD) in subsequent pregnancy. DESIGN: Population-based cohort study. SETTING: Data of the National Health Insurance Claims Database and a national health-screening programme for infants and children in South Korea. POPULATION: Women who had their first singleton delivery in 2010 and a subsequent second singleton delivery between 2011 and 2015. METHODS: Multivariable analysis adjusting for maternal age and interval between first and second deliveries was used to assess the risk of PTD based on PTD, TPL followed by term delivery, and term delivery in the first pregnancy. MAIN OUTCOME MEASURES: The risk of PTD during the second pregnancy. RESULTS: This study included 115 629 women with two consecutive deliveries during the study period. Spontaneous PTD rates in the second pregnancy were 7.71, 2.22 and 1.02% in women with PTD, TPL followed by term delivery, and term delivery in the first pregnancy, respectively. Threatened preterm labour followed by term delivery in the first pregnancy was associated with increased risk of PTD in the subsequent pregnancy after adjustment for potential confounding factors (adjusted odds ratio 2.21; 95% CI 1.76-2.78). CONCLUSION: Although women with a history of TPL followed by term delivery had a lower risk of PTD during a subsequent pregnancy compared with those with history of previous PTD, they still had a significantly increased risk of PTD compared with those who delivered at term without TPL. TWEETABLE ABSTRACT: The history of threatened preterm labour followed by term delivery is related to increased risk of subsequent spontaneous preterm delivery.

Classifying pain in transoral endoscopic thyroidectomy.

PURPOSES: Knowledge of visual analog scale (VAS) pain assessment for transoral endoscopic thyroidectomy vestibular approach (TOETVA) is limited. The purpose of this analysis was to classify the postoperative discomfort scores in patients undergoing TOETVA compared to open thyroidectomy. METHODS: Observational clinical study of patients who underwent thyroidectomy by VAS pain assessment from September 2016 to March 2017. Patients were stratified into two groups: patients eligible for TOETVA (Group TOETVA) and non-candidates for endoscopic intervention (open thyroidectomy approach-OTA). VAS was recorded in the recovery room, at 24 h, + 2, + 5, + 15, + 30, + 90 days, and 6 months after surgery. Pain assessment was stratified in VAS-lower lip, VAS-chin, VAS-jaw, VAS-anterior neck, VAS-cervical/back, VAS-swallowing, VAS-brushing, VAS-speaking, and VAS-shaving. Secondary outcome assessed were analgesic rescue dose, morbidity, operative notes, hospital stay, and histopathology. RESULTS: 41 TOETVA and 45 OTA constituted the analysis. There were differences between the TOETVA and OTA for age, gland volume, mean nodule diameter, coexistence thyroiditis, bilateral procedures, and use of drain. Operative time was longer in TOETVA. Results indicated that TOETVA was associated with reduced neck, cervical back, and swallowing VAS scores in the 24 h after surgery. Conversely, jaw and brushing teeth resulted in higher VAS score in TOETVA group. OTA patients never experienced lower lip or chin pain. The use of rescue analgesics did not differ between the two groups. CONCLUSIONS: VAS was used to measure treatment outcome in TOETVA. VAS scores achieved overall a minimal clinical importance difference from the two procedures. There appears to be both a short- and long-term different range of interpretations of pain between TOETVA and OTA.

Home-based intervention to test and start (HITS) protocol: a cluster-randomized controlled trial to reduce HIV-related mortality in men and HIV incidence in women through increased coverage of HIV treatment.

BACKGROUND: To realize the full benefits of treatment as prevention in many hyperendemic African contexts, there is an urgent need to increase uptake of HIV testing and HIV treatment among men to reduce the rate of HIV transmission to (particularly young) women. This trial aims to evaluate the effect of two interventions - micro-incentives and a tablet-based male-targeted HIV decision support application - on increasing home-based HIV testing and linkage to HIV care among men with the ultimate aim of reducing HIV-related mortality in men and HIV incidence in young women. METHODS/DESIGN: This is a cluster randomized trial of 45 communities (clusters) in a rural area in the uMkhanyakude district of KwaZulu Natal, South Africa (2018-2021). The study is built upon the Africa Health Research Institute (AHRI)'s HIV testing platform, which offers annual home-based rapid HIV testing to individuals aged 15 years and above. In a 2 × 2 factorial design, individuals aged ≥15 years living in the 45 clusters are randomly assigned to one of four arms: i) a financial micro-incentive (food voucher) (n = 8); ii) male-targeted HIV specific decision support (EPIC-HIV) (n = 8); iii) both the micro incentives and male-targeted decision support (n = 8); and iv) standard of care (n = 21). The EPIC-HIV application is developed and delivered via a tablet to encourage HIV testing and linkage to care among men. A mixed method approach is adopted to supplement the randomized control trial and meet the study aims. DISCUSSION: The findings of this trial will provide evidence on the feasibility and causal impact of two interventions - micro-incentives and a male-targeted HIV specific decision support - on uptake of home-based HIV testing, linkage to care, as well as population health outcomes including population viral load, HIV related mortality in men, and HIV incidence in young women (15-30 years of age). TRIAL REGISTRATION: This trial was registered on 28 November 2018 on, identifier https://clinicaltrials.gov/ .

Src-type tyrosine kinase p56lck is critical for thymic stromal lymphopoietin-induced allergic rhinitis.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a regulator of mast cell-mediated allergic inflammatory reactions, but the manner in which TSLP contributes to allergic rhinitis (AR) remains unclear. OBJECTIVE: Here, we sought to determine that TSLP plays a crucial role in AR by interacting with Src-type tyrosine kinase p56lck and STAT6 and promoting mast cells degranulation. METHODS: The effects of TSLP on mast cell degranulation and AR were analysed in human mast cell line (HMC-1 cells), ovalbumin (OVA)-induced AR animal model, and human subjects. Small interfering RNA experiments were performed in HMC-1 cells and OVA-induced AR model. Immune responses were analysed by enzyme-linked immunosorbent assay, Western blotting, immunoprecipitation, and histological studies. RESULTS: Thymic stromal lymphopoietin levels and mast cell-derived p56lck activation were elevated in human subjects with AR, and in AR mice, exogenous TSLP accelerated TH2-allergic inflammatory reactions by up-regulating p56lck and STAT6. On the other hand, depletion of TSLP, p56lck, and STAT6 ameliorated clinical symptoms in AR mice. The selective inhibitor of p56lck, damnacanthal, inhibits AR reactions. CONCLUSION: Collectively, these observations suggest a role for TSLP/p56lck/STAT6 in AR and offer insight into potential therapeutic strategies.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.

Systemic lupus erythematosus is a risk factor for cardiovascular disease: a nationwide, population-based study in Korea.

OBJECTIVE: To investigate the incidence and clinical significance of cardiovascular disease in systemic lupus erythematosus patients. METHODS: We included systemic lupus erythematosus patients ( n = 18,575) without previous cardiovascular disease and age- and sex-matched individuals without systemic lupus erythematosus (controls; n = 92,875) from the Korean National Health Insurance Service database (2008-2014). Both cohorts were followed up for incident cardiovascular disease and death until 2015. RESULTS: During follow up, myocardial infarction occurred in 203 systemic lupus erythematosus patients and 325 controls (incidence rate: 1.76 and 0.56 per 1000 person-years, respectively), stroke occurred in 289 patients and 403 controls (incidence rate: 2.51 and 0.70 per 1000 person-years, respectively), heart failure occurred in 358 patients and 354 controls (incidence rate 3.11 and 0.61 per 1000 person-years, respectively), and death occurred in 744 patients and 948 controls (incidence rate 6.54 and 1.64 per 1000 person-years, respectively). Patients with systemic lupus erythematosus had higher risks for myocardial infarction (hazard ratio: 2.74, 95% confidence interval: 2.28-3.37), stroke (hazard ratio: 3.31, 95% confidence interval: 2.84-3.86), heart failure (hazard ratio: 4.60, 95% confidence interval: 3.96-5.35), and cardiac death (hazard ratio: 3.98, 95% confidence interval: 3.61-4.39). CONCLUSIONS: Here, systemic lupus erythematosus was an independent risk factor for cardiovascular disease, thus cardiac assessment and management are critical in systemic lupus erythematosus patients.

Effects of BMP-2 on the osteogenic differentiation of bone marrow stem cells in fibrous dysplasia.

OBJECTIVES: The purpose of this study was to evaluate the effects of BMP-2 on bone-grafting procedures for the treatment of fibrous dysplasia based on in vitro and in vivo experiments. SUBJECTS AND METHODS: Proliferation of stem cells was determined by colony-forming assay, CCK-8 assay and BrdU staining. OCT4 and NANOG expression was analysed by flow cytometry and immunocytochemistry. Osteogenic differentiation was assessed by measuring ALP activity, Alizarin red S staining and in vivo transplantation. Gene expression of the osteogenic markers, osteocalcin and type 1 collagen, was determined by RT-PCR. RESULTS: FD-BMSCs showed few calcium deposits and low ALP activity. Bone formation by transplanted FD-BMSCs was also suppressed relative to that of normal BMSCs. However, BMP-2 treatment enhanced osteogenic differentiation of FD-BMSCs mixed with normal BMSCs in vitro and in vivo. Overall, BMP-2 treatment promoted osteogenic differentiation of FD-BMSCs mixed with normal BMSCs. CONCLUSIONS: In patients with FD, stem cells in affected bone are influenced by the mutation, resulting in weak bone formation with the proliferation of immature osteogenic cells. Current treatment of FD involves surgical removal of excess bulk lesions, which can cause facial disfigurement. Our results suggest that BMP-2 application is a good adjunctive modality to the surgical treatment of patients with FD.