Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and ...subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis.
We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls.
SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV.
The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens.
US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.
Innate lymphoid cells (ILCs) are guardians of mucosal immunity, yet the transcriptional networks that support their function remain poorly understood. We used inducible combinatorial deletion of key ...transcription factors (TFs) required for ILC development (RORγt, RORα and T-bet) to determine their necessity in maintaining ILC3 identity and function. Both RORγt and RORα were required to preserve optimum effector functions; however, RORα was sufficient to support robust interleukin-22 production among the lymphoid tissue inducer (LTi)-like ILC3 subset, but not natural cytotoxicity receptor (NCR)
ILC3s. Lymphoid tissue inducer-like ILC3s persisted with only selective loss of phenotype and effector functions even after the loss of both TFs. In contrast, continued RORγt expression was essential to restrain transcriptional networks associated with type 1 immunity within NCR
ILC3s, which coexpress T-bet. Full differentiation to an ILC1-like population required the additional loss of RORα. Together, these data demonstrate how TF networks integrate within mature ILCs after development to sustain effector functions, imprint phenotype and restrict alternative differentiation programs.
CMOS‐compatible nonlinear optics platforms with negligible nonlinear losses and high nonlinearity are of great merit. Silicon, silicon nitride and Hydex glass have made significant headway in ...nonlinear optical signal processing, though none of these platforms possesses the highly sought after combination of high nonlinearity and negligible nonlinear losses. In this manuscript, we present a nonlinear optics platform based on silicon‐rich nitride, deposited at a low temperature of 250°C compatible with back‐end CMOS processing. The silicon‐rich nitride is designed and engineered in composition to have a bandgap of 2.05 eV, such that the two‐photon absorption edge is well below 1.55 μm. The designed and developed waveguides have a nonlinear parameter of 550 W−1/m, 500 times larger than that in silicon nitride waveguides, while at the same time not possessing two‐photon and free‐carrier losses. Using 500‐fs pulses, we generate supercontinuum exceeding 0.6 of an octave.
We present a nonlinear optics platform based on silicon rich nitride, deposited at 250°C and compatible with back‐end CMOS processing. The silicon rich nitride is engineered to have a band gap of 2.05 eV, such that the two photon absorption edge is well below 1.55 μm. Developed waveguides have a nonlinear parameter of 550W−1/m and negligible nonlinear losses. Using 500 fs pulses, we generate supercontinuum exceeding 0.6 of an octave.
CMOS platforms operating at the telecommunications wavelength either reside within the highly dissipative two-photon regime in silicon-based optical devices, or possess small nonlinearities. Bandgap ...engineering of non-stoichiometric silicon nitride using state-of-the-art fabrication techniques has led to our development of USRN (ultra-silicon-rich nitride) in the form of Si7 N3 , that possesses a high Kerr nonlinearity (2.8 × 10-13 cm2 W-1 ), an order of magnitude larger than that in stoichiometric silicon nitride. Here we experimentally demonstrate high-gain optical parametric amplification using USRN, which is compositionally tailored such that the 1,550 nm wavelength resides above the two-photon absorption edge, while still possessing large nonlinearities. Optical parametric gain of 42.5 dB, as well as cascaded four-wave mixing with gain down to the third idler is observed and attributed to the high photon efficiency achieved through operating above the two-photon absorption edge, representing one of the largest optical parametric gains to date on a CMOS platform.
Background:
The increasing popularity of distance running has been accompanied by an increase in running-related injuries, such that up to 85% of novice runners incur an injury in a given year. ...Previous studies have used a gait retraining program to successfully lower impact loading, which has been associated with many running ailments. However, softer footfalls may not necessarily prevent running injury.
Purpose:
To examine vertical loading rates before and after a gait retraining program and assess the effectiveness of the program in reducing the occurrence of running-related injury across a 12-month observation period.
Study Design:
Randomized controlled trial; Level of evidence, 1.
Methods:
A total of 320 novice runners from the local running club completed this study. All the participants underwent a baseline running biomechanics evaluation on an instrumented treadmill with their usual running shoes at 8 and 12 km/h. Participants were then randomly assigned to either the gait retraining group or the control group. In the gait retraining group (n = 166), participants received 2 weeks of gait retraining with real-time visual feedback. In the control group (n = 154), participants received treadmill running exercise but without visual feedback on their performance. The training time was identical between the 2 groups. Participants’ running mechanics were reassessed after the training, and their 12-month posttraining injury profiles were tracked by use of an online surveillance platform.
Results:
A significant reduction was found in the vertical loading rates at both testing speeds in the gait retraining group (P < .001, Cohen’s d > 0.99), whereas the loading rates were either similar or slightly increased in the control group after training (P = .001 to 0.461, Cohen’s d = 0.03 to −0.14). At 12-month follow-up, the occurrence of running-related musculoskeletal injury was 16% and 38% in the gait retraining and control groups, respectively. The hazard ratio between gait retraining and control groups was 0.38 (95% CI, 0.25-0.59), indicating a 62% lower injury risk in gait-retrained runners compared with controls.
Conclusion:
A 2-week gait retraining program is effective in lowering impact loading in novice runners. More important, the occurrence of injury is 62% lower after 2 weeks of running gait modification.
Registration:
HKUCTR-1996 (University of Hong Kong Clinical Trials Registry).
Silicon-rich nitride films are developed and explored using an inductively coupled plasma chemical vapor deposition system at low temperature of 250 °C with an ammonia-free gas chemistry. The ...refractive index of the developed silicon-rich nitride films can increase from 2.2 to 3.08 at 1550 nm wavelength while retaining a near-zero extinction coefficient when the amount of silane increases. Energy dispersive spectrum analysis gives the silicon to nitrogen ratio in the films. Atomic force microscopy shows a very smooth surface, with a surface roughness root-mean-square of 0.27 nm over a 3 μm × 3 μm area of the 300 nm thick film with a refractive index of 3.08. As an application example, the 300 nm thick silicon-rich nitride film is then patterned by electron beam lithography and etched using inductively coupled plasma system to form thin-film micro/nano waveguides, and the waveguide loss is characterized.
Objective
To estimate the accuracy of transvaginal ultrasound (TVS) measurement of endometrial thickness (ET) in diagnosing endometrial cancer in postmenopausal women with vaginal bleeding (PMB).
...Design
Retrospective cohort study.
Setting
One‐stop PMB clinic in a Hong Kong teaching hospital.
Population
A cohort of 4383 women with PMB.
Methods
Transvaginal ultrasonic measurement of ET and endometrial biopsies were obtained in women presenting with PMB between 2002 and 2013. Endometrial histology was used as the reference standard to calculate accuracy estimates.
Main outcome measures
Accuracy data for TVS ET presented as sensitivity, specificity, and area under the receiver operator characteristic (ROC) curve.
Results
Endometrial cancer was diagnosed in 3.8% of women. The median ET in those with endometrial cancer was significantly higher than those with benign conditions (15.7 versus 3.2 mm, P < 0.001). The area under the ROC curve was 0.92 (95% CI 0.89–0.94). The sensitivity for the detection of endometrial cancer at 3‐, 4‐, and 5‐mm cut‐offs were 97.0% (95% CI 94.5–99.6%), 94.1% (95% CI 90.5–97.6%), and 93.5% (95% CI 89.7–97.2%), respectively. The corresponding estimates of specificity at these thresholds were 45.3% (95% CI 43.8–46.8%), 66.8% (65.4–68.2%), and 74.0% (72.7–75.4%).
Conclusions
Transvaginal ultrasound using a 3‐mm cut‐off has high sensitivity for detecting endometrial cancer and can identify women with PMB who are highly unlikely to have endometrial cancer, thereby avoiding more invasive endometrial biopsy.
Events mediating transformation from the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are unknown. We analyzed gene expression data sets generated ...on the Affymetrix U133 platform from 22 MGUS and 101 MM patients using gene-set enrichment analysis. Genes overexpressed in MM were enriched for cell cycle, proliferation and MYC activation gene sets. Upon dissecting the relationship between MYC and cell-cycle gene sets, we identified and validated an MYC activation signature dissociated from proliferation. Applying this signature, MYC is activated in 67% of myeloma, but not in MGUS. This was further confirmed by immunohistochemistry (IHC) using membrane CD138 and nuclear MYC double staining. We also showed that almost all tumors with RAS mutations expressed the MYC activation signature, and multiple mechanisms may be involved in activating MYC. MYC activation, whether assessed by gene-expression signature or IHC, is associated with hyperdiploid MM and shorter survival even in tumors that are not proliferative. Bortezomib treatment is able to overcome the survival disadvantage in patients with MYC activation.
Early onset of myopia is associated with high myopia later in life, and myopia is irreversible once developed.
To evaluate the efficacy of low-concentration atropine eyedrops at 0.05% and 0.01% ...concentration for delaying the onset of myopia.
This randomized, placebo-controlled, double-masked trial conducted at the Chinese University of Hong Kong Eye Centre enrolled 474 nonmyopic children aged 4 through 9 years with cycloplegic spherical equivalent between +1.00 D to 0.00 D and astigmatism less than -1.00 D. The first recruited participant started treatment on July 11, 2017, and the last participant was enrolled on June 4, 2020; the date of the final follow-up session was June 4, 2022.
Participants were assigned at random to the 0.05% atropine (n = 160), 0.01% atropine (n = 159), and placebo (n = 155) groups and had eyedrops applied once nightly in both eyes over 2 years.
The primary outcomes were the 2-year cumulative incidence rate of myopia (cycloplegic spherical equivalent of at least -0.50 D in either eye) and the percentage of participants with fast myopic shift (spherical equivalent myopic shift of at least 1.00 D).
Of the 474 randomized patients (mean age, 6.8 years; 50% female), 353 (74.5%) completed the trial. The 2-year cumulative incidence of myopia in the 0.05% atropine, 0.01% atropine, and placebo groups were 28.4% (33/116), 45.9% (56/122), and 53.0% (61/115), respectively, and the percentages of participants with fast myopic shift at 2 years were 25.0%, 45.1%, and 53.9%. Compared with the placebo group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 24.6% 95% CI, 12.0%-36.4%) and percentage of patients with fast myopic shift (difference, 28.9% 95% CI, 16.5%-40.5%). Compared with the 0.01% atropine group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 17.5% 95% CI, 5.2%-29.2%) and percentage of patients with fast myopic shift (difference, 20.1% 95% CI, 8.0%-31.6%). The 0.01% atropine and placebo groups were not significantly different in 2-year cumulative myopia incidence or percentage of patients with fast myopic shift. Photophobia was the most common adverse event and was reported by 12.9% of participants in the 0.05% atropine group, 18.9% in the 0.01% atropine group, and 12.2% in the placebo group in the second year.
Among children aged 4 to 9 years without myopia, nightly use of 0.05% atropine eyedrops compared with placebo resulted in a significantly lower incidence of myopia and lower percentage of participants with fast myopic shift at 2 years. There was no significant difference between 0.01% atropine and placebo. Further research is needed to replicate the findings, to understand whether this represents a delay or prevention of myopia, and to assess longer-term safety.
Chinese Clinical Trial Registry: ChiCTR-IPR-15006883.
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