We present an analysis of the first 10 weeks of the severe acute respiratory syndrome (SARS) epidemic in Hong Kong. The epidemic to date has been characterized by two large clusters-initiated by two ...separate "super-spread" events (SSEs)-and by ongoing community transmission. By fitting a stochastic model to data on 1512 cases, including these clusters, we show that the etiological agent of SARS is moderately transmissible. Excluding SSEs, we estimate that 2.7 secondary infections were generated per case on average at the start of the epidemic, with a substantial contribution from hospital transmission. Transmission rates fell during the epidemic, primarily as a result of reductions in population contact rates and improved hospital infection control, but also because of more rapid hospital attendance by symptomatic individuals. As a result, the epidemic is now in decline, although continued vigilance is necessary for this to be maintained. Restrictions on longer range population movement are shown to be a potentially useful additional control measure in some contexts. We estimate that most currently infected persons are now hospitalized, which highlights the importance of control of nosocomial transmission.
Postradiation oral cavity squamous cell carcinoma (OCSCC) is a common secondary malignant neoplasm affecting survivors of head and neck cancer who underwent radiotherapy. The clinical, pathologic, ...and immune-related features of postradiation OCSCC are poorly characterized, and treatment options are limited because of surgical difficulty and high morbidity associated with reirradiation.
To determine whether postradiation OCSCC has distinctive clinical, pathologic, and immune-related features compared with demographic-matched sporadic OCSCC.
This retrospective matched cohort study was conducted at a single tertiary oncology center in Hong Kong. Participants included consecutive patients with OCSCC diagnosed between 2000 and 2020. Patients with postradiation OCSCC were matched with patients with sporadic OCSCC using age, year of diagnosis, sex, and anatomic subsites. Data analysis was performed from July to December 2022.
Head and neck irradiation involving the oral cavity before the diagnosis of OCSCC.
The primary outcomes were relapse pattern, survival, and causes of death. Pathologic features; immunohistochemical staining for programmed death-ligand 1, PD-1, MSH6, PMS2, FOXP3, and Ki67; and mRNA expression of 31 immune-related genes were also analyzed.
A total of 173 patients, 60 with postradiation OCSCC (median IQR age, 63.8 53.0-71.7 years; 43 men 71.7%) and 113 with sporadic OCSCC (median IQR age, 64.4 52.8-70.6 years; 83 men 73.5%), were included. Patients with postradiation OCSCC had a higher proportion of N0 disease than those with sporadic OCSCC (50 patients 83.3% vs 56 patients 49.6%). With a median (IQR) follow-up of 10.2 (1.2-20.5) years, the 10-year relapse-free survival rates were lower in patients with postradiation OCSCC than sporadic OCSCC (29.6% 95% CI, 17.1%-43.2% vs 52.4% 95% CI, 41.8%-62.0%; P = .04), and the same was true for overall survival (30.5% 95% CI, 17.6%-44.4% vs 52.3% 95% CI, 41.4%-62.1%; P = .03). All relapses in patients with postradiation OCSCC were locoregional, whereas 35.2% of relapses (12 of 34 patients) in patients with sporadic OCSCC were distant. Despite similar 10-year disease-specific survival rates between the 2 groups (68.8% 95% CI, 55.8%-81.0% vs 67.1% 95% CI, 57.5%-76.5%; P = .91), patients with postradiation OCSCC had excess mortality due to pneumonia and cerebrovascular events. Postradiation OCSCC exhibited more adverse pathologic features (perineural invasion, worse pattern of invasion, and tumor budding), higher PD-1 expression, and higher gene expression of CD4 and TGF-β compared with sporadic OCSCC.
This retrospective matched cohort study found distinctive pathologic characteristics and relapse patterns of postradiation OCSCC compared with sporadic OCSCC, which may be attributable to the lack of adjuvant radiotherapy, aggressive biologic phenotype, and different host immune response. Further exploration of the role of immune checkpoint therapy may be justified.
Pulmonary vein isolation by cryoballoon ablation is an accepted method of treating atrial fibrillation. Little data exist regarding factors affecting late electrical reconnection of pulmonary veins ...following cryoballoon ablation.
To investigate factors determining pulmonary vein reconnection in patients undergoing repeat catheter ablation for recurrent atrial fibrillation following cryoballoon ablation.
Fifty-one consecutive patients undergoing repeat catheter ablation for recurrent atrial fibrillation following initial cryoballoon ablation underwent retrospective assessment of initial cryoablation characteristics, including balloon and vein sizes, venogram occlusion score, balloon freezing time from 0 to -30 °C, nadir temperature, and balloon warming time from -30 to +15 °C, recorded during the initial cryoballoon procedure.
Of 199 veins assessed, 91 had reconnected (1.8 per patient). Balloon warming time (odds ratio OR 3.21; 95% confidence interval CI 2.00-5.13; P < .0001), nadir temperature (OR 1.94; 95% CI 1.42-2.66; P < .0001), vein occlusion score (OR 1.74; 95% CI 1.29-2.34; P = .0003), and balloon freezing time (OR 1.58; 95% CI 1.03-2.42; P = .037) predicted pulmonary vein reconnection. On multivariate analysis, balloon warming time (OR 3.71; 95% CI 2.2-6.24; P ≤ .0001), pulmonary vein size (OR 1.63; 95% CI 1.08-2.43; P = .020), and vein occlusion score (OR 1.48; 95% CI 1.06-2.08; P = .021) remained statistically significant independent predictors of pulmonary vein reconnection. The receiver operating characteristic for the multivariate model yielded an area under the curve of 0.82.
Balloon warming time, vein occlusion score, and pulmonary vein size predict pulmonary vein reconnection. Balloon warming time was the most important predictive factor, and the manipulation of balloon warming may be a novel therapeutic strategy for improving outcomes of cryoballoon ablation for atrial fibrillation.
The pulmonary nodule is the most common manifestation of lung cancer, the most deadly of all cancers. Most small pulmonary nodules are benign, however, and currently the growth rate of the nodule ...provides for one of the most accurate noninvasive methods of determining malignancy. In this paper, we present methods for measuring the change in nodule size from two computed tomography image scans recorded at different times; from this size change the growth rate may be established. The impact of partial voxels for small nodules is evaluated and isotropic resampling is shown to improve measurement accuracy. Methods for nodule location and sizing, pleural segmentation, adaptive thresholding, image registration, and knowledge-based shape matching are presented. The latter three techniques provide for a significant improvement in volume change measurement accuracy by considering both image scans simultaneously. Improvements in segmentation are evaluated by measuring volume changes in benign or slow growing nodules. In the analysis of 50 nodules, the variance in percent volume change was reduced from 11.54% to 9.35% (p=0.03) through the use of registration, adaptive thresholding, and knowledge-based shape matching.
Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.9% of ...PLGAs but not in other salivary gland tumors. Functional studies demonstrated that this kinase-activating alteration likely constitutes a driver of PLGA.
We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple ...intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.
FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials ...in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line.
The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL
(≥0.6 to <5 low-titre, ≥5 high titre).
A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa.
mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null
mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null
mutations developed inhibitors.
In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null
mutations.
Given the unceasing worldwide surge in COVID-19 cases, there is an imperative need to develop highly specific and sensitive serology assays to define exposure to Severe Acute Respiratory Syndrome ...Coronavirus 2 (SARS-CoV-2).
Pooled plasma samples from PCR positive COVID-19 patients were used to identify linear B-cell epitopes from a SARS-CoV-2 peptide library of spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins by peptide-based ELISA. Hit epitopes were further validated with 79 COVID-19 patients with different disease severity status, 13 seasonal human CoV, 20 recovered SARS patients and 22 healthy donors.
Four immunodominant epitopes, S14P5, S20P2, S21P2 and N4P5, were identified on the S and N viral proteins. IgG responses to all identified epitopes displayed a strong detection profile, with N4P5 achieving the highest level of specificity (100%) and sensitivity (>96%) against SARS-CoV-2. Furthermore, the magnitude of IgG responses to S14P5, S21P2 and N4P5 were strongly associated with disease severity.
IgG responses to the peptide epitopes can serve as useful indicators for the degree of immunopathology in COVID-19 patients, and function as higly specific and sensitive sero-immunosurveillance tools for recent or past SARS-CoV-2 infections. The flexibility of these epitopes to be used alone or in combination will allow for the development of improved point-of-care-tests (POCTs).
Biomedical Research Council (BMRC), the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from Agency of Science, Technology and Research (A*STAR), and National Medical Research Council (NMRC) COVID-19 Research fund (COVID19RF-001) and CCGSFPOR20002. ATR is supported by the Singapore International Graduate Award (SINGA), A*STAR.
Little is known about the extracellular matrix (ECM) during progression of AD pathology. Brain ECM is abundant in hyaluronan (HA), a non-sulfated glycosaminoglycan synthesized by HA synthases (HAS) ...1-3 in a high molecular weight (MW) form that is degraded into lower MW fragments. We hypothesized that pathologic severity of AD is associated with increases in HA and HA-associated ECM molecules. To test this hypothesis, we assessed HA accumulation and size; HA synthases (HAS) 1-3; and the HA-stabilizing hyaladherin, TSG-6 in parietal cortex samples from autopsied research subjects with not AD (CERAD = 0, Braak = 0- II, n = 12-21), intermediate AD (CERAD = 2, Braak = III-IV, n = 13-18), and high AD (CERAD = 3, Braak = V-VI, n = 32-40) neuropathologic change. By histochemistry, HA was associated with deposits of amyloid and tau, and was also found diffusely in brain parenchyma, with overall HA quantity (measured by ELSA) significantly greater in brains with high AD neuropathology. Mean HA MW was similar among the samples. HAS2 and TSG-6 mRNA expression, and TSG-6 protein levels were significantly increased in high AD and both molecules were present in vasculature, NeuN-positive neurons, and Iba1-positive microglia. These results did not change when accounting for gender, advanced age (≥ 90 years versus <90 years), or the clinical diagnosis of dementia. Collectively, our results indicate a positive correlation between HA accumulation and AD neuropathology, and suggest a possible role for HA synthesis and metabolism in AD progression.
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