Abstract
Background
Mass vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing amidst widespread transmission during the coronavirus disease-2019 (COVID-19) ...pandemic. Disease phenotypes of SARS-CoV-2 exposure occurring around the time of vaccine administration have not been described.
Methods
Two-dose (14 days apart) vaccination regimen with formalin-inactivated whole virion SARS-CoV-2 in golden Syrian hamster model was established. To investigate the disease phenotypes of a 1-dose regimen given 3 days prior (D-3), 1 (D1) or 2 (D2) days after, or on the day (D0) of virus challenge, we monitored the serial clinical severity, tissue histopathology, virus burden, and antibody response of the vaccinated hamsters.
Results
The 1-dose vaccinated hamsters had significantly lower clinical disease severity score, body weight loss, lung histology score, nucleocapsid protein expression in lung, infectious virus titers in the lung and nasal turbinate, inflammatory changes in intestines, and a higher serum neutralizing antibody or IgG titer against the spike receptor-binding domain or nucleocapsid protein when compared to unvaccinated controls. These improvements were particularly noticeable in D-3, but also in D0, D1, and even D2 vaccinated hamsters to varying degrees. No increased eosinophilic infiltration was found in the nasal turbinate, lung, and intestine after virus challenge. Significantly higher serum titer of fluorescent foci microneutralization inhibition antibody was detected in D1 and D2 vaccinated hamsters at day 4 post-challenge compared to controls despite undetectable neutralizing antibody titer.
Conclusions
Vaccination just before or soon after exposure to SARS-CoV-2 does not worsen disease phenotypes and may even ameliorate infection.
Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means ...to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.
Abstract Purpose We sought to determine the clinical significance of aspirin resistance measured by a point-of-care assay in stable patients with coronary artery disease (CAD). Methods We used the ...VerifyNow Aspirin (Accumetrics Inc, San Diego, Calif) to determine aspirin responsiveness of 468 stable CAD patients on aspirin 80 to 325 mg daily for ≥4 weeks. Aspirin resistance was defined as an Aspirin Reaction Unit ≥550. The primary outcome was the composite of cardiovascular death, myocardial infarction (MI), unstable angina requiring hospitalization, stroke, and transient ischemic attack. Results Aspirin resistance was noted in 128 (27.4%) patients. After a mean follow-up of 379 ± 200 days, patients with aspirin resistance were at increased risk of the composite outcome compared to patients who were aspirin-sensitive (15.6% vs 5.3%, hazard ratio HR 3.12, 95% confidence intervals CI, 1.65-5.91, P < .001). Cox proportional hazard regression modeling identified aspirin resistance, diabetes, prior MI, and a low hemoglobin to be independently associated with major adverse long-term outcomes (HR for aspirin resistance 2.46, 95% CI, 1.27-4.76, P = .007). Conclusions Aspirin resistance, defined by an aggregation-based rapid platelet function assay, is associated with an increased risk of adverse clinical outcomes in stable patients with CAD.
Airborne transmission of SARS-CoV-2 has been increasingly recognized in the outbreak of COVID-19, especially with the Omicron variant. We investigated an outbreak due to Omicron variant in a ...restaurant. Besides epidemiological and phylogenetic analyses, the secondary attack rates of customers of restaurant-related COVID-19 outbreak before (Outbreak R1) and after enhancement of indoor air dilution (Outbreak R2) were compared. On 27th December 2021, an index case stayed in restaurant R2 for 98 min. Except for 1 sitting in the same table, six other secondary cases sat in 3 corners at 3 different zones, which were served by different staff. The median exposure time was 34 min (range: 19–98 min). All 7 secondary cases were phylogenetically related to the index. Smoke test demonstrated that the airflow direction may explain the distribution of secondary cases. Compared with an earlier COVID-19 outbreak in another restaurant R1 (19th February 2021), which occurred prior to the mandatory enhancement of indoor air dilution, the secondary attack rate among customers in R2 was significantly lower than that in R1 (3.4%, 7/207 vs 28.9%, 22/76, p<0.001). Enhancement of indoor air dilution through ventilation and installation of air purifier could minimize the risk of SARS-CoV-2 transmission in the restaurants.
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•SARS-CoV-2 is considered as a hazardous material.•Omicron variant is transmitted by airborne route.•Restaurant is a high-risk area for SARS-CoV-2 outbreak.•Enhanced indoor air dilution minimizes the number of infected cases.
Abstract Background and Aims Genetic testing has increasingly been employed to provide definitive diagnoses and prognostic information in patients with Autosomal Dominant Polycystic Kidney Disease ...(ADPKD). We aim to explore the genetic landscape of ADPKD in a Chinese cohort utilizing whole genome sequencing and study its real-world clinical utility. Method From 1st January 2022 to 31st March 2023, we recruited 50 adult Chinese patients who had the clinical diagnosis of ADPKD followed up at Queen Mary Hospital and consented to the study protocol. The study was approved by the University Institution Review Board and local ethics committees. Genomic DNA was isolated from samples obtained from patients per standard protocol. Whole-genome sequencing was performed and analysed through the germline analysis pipeline. Diagnostic analysis was performed per American College of Medical Genetics (ACMG) guidelines and ClinGen variant curation expert panel specifications. Diagnostic variants were defined as those classified as ‘pathogenic’ or ‘likely pathogenic’. Potential clinical utility of genetic findings were studied case-by-case based on the Kidney Disease Improving Global Outcomes (KDIGO) 2023 Clinical Practice Guideline for the Evaluation, Management and Treatment of ADPKD. Results Among the 50 unrelated probands with ADPKD, half were males and the mean age at presentation was 38. 38% patients had incidental finding of kidney cysts on abdominal imaging performed for unrelated symptoms or health screening, 32% presented for screening due to positive family history and only 30% presented with typical symptoms of ADPKD. Cystic complications were present in 30%, with cyst haemorrhage being the most common, followed by kidney stones, cyst rupture and infection. 80% patients also had liver cysts and none had a history of cerebral aneurysms. The majority of our cohort (72%) had a family history of ADPKD. We identified diagnostic variants in 35 individuals, reaching a diagnostic yield of 70%. Diagnostic variants were identified in PKD1 (20/35), PKD2 (11/35), IFT140 (3/35) and ALG9 (1/35). The majority of diagnostic variants were protein-truncating (32/35), while non-truncating variants consisted of 1 in-frame deletion and 2 missense variants in PKD1. We identified 3 copy number variation:NC_000016.10:g.2110587_2111851del,NC_000016.10:g.2132339_2137621del,NC_000016.10:g.2036427_2101117del. The genetic findings allowed physicians to make definitive diagnosis in 9 patients with negative family history of ADPKD. The genetic findings provided important prognostic information as protein-truncating variants in PKD1 or PKD2 were associated with more severe disease compared to non-truncating variants. For the 3 patients harbouring heterozygous pathogenic variants in IFT140 (NM_014714.4:c.2659G>T, NM_014714.4:c.3780del, NM_014714.4:c.1035_1036del), they demonstrated a milder PKD phenotype with stable kidney function, normal kidneys size and absence of liver cysts 10 years after the diagnosis. The patient with heterozygous likely pathogenic ALG9 variant (NM_024740.2:c.1225del) also had milder PKD phenotype with normal kidney function and normal sized kidneys on USG 5 years after the diagnosis. In another male patient with young hypertension who was classified as Mayo Class 1C according to kidney imaging, identifying the pathogenic protein-truncating variant in PKD1 (NM_001009944.3:c.7288C>T) would render him eligible to tolvaptan treatment in view of the high PROPKD score (7). Furthermore, the genetic findings enabled an earlier diagnosis in a number of family members by cascade testing and genetic results were important to identify suitable living-related kidney donors. Conclusion Genetic testing utilizing whole genome sequencing has multiple clinical utility in ADPKD patients. It could provide a definitive diagnosis in those with atypical presentation or without family history, inform prognosis, guide treatment, determine living-related donor suitability and allow earlier diagnosis in other family members.
The combination of aspirin, clopidogrel, and enoxaparin (combination therapy) is the standard treatment for acute coronary syndrome but is associated with gastrointestinal bleeding. However, ...information in this area is scarce.
This retrospective study aimed to determine the incidence of upper gastrointestinal bleeding in a real-life situation. The effect of proton pump inhibitor (PPI) treatment was also analyzed.
From January 2002 to December 2006, all patients receiving combination therapy were analyzed. The end point was the occurrence of upper gastrointestinal bleeding during combination therapy or within 7 days of stopping enoxaparin.
The patient group consisted of 666 patients (age 72.1 +/- 12.6 yr). Gastrointestinal bleeding occurred in 18 (2.7%) patients. The overall hospital mortality was 4.1% (27 patients). A cardiac event was the major cause (N = 24, 3.6%). Only one patient died of massive gastrointestinal bleeding (0.15%). Multiple logistic regression analysis demonstrated that previous peptic ulcer, cardiogenic shock, and the lack of PPI coprescription were significant risk factors for gastrointestinal bleeding. The age-adjusted odds ratio (95% confidence interval) for gastrointestinal bleeding was 5.07 (1.31-16.58) for previous peptic ulcer, 21.41 (2.56-146.68) for cardiogenic shock, and 0.068 (0.010-0.272) for the coprescription with a PPI.
In real life, the incidence of gastrointestinal bleeding associated with the combination of aspirin, clopidogrel, and enoxaparin therapy was estimated to be 2.7%. Previous peptic ulcer disease or cardiogenic shock were significant independent risk factors. Coprescription with a PPI can significantly reduce the risk.
We sought to investigate the association of aspirin dose and aspirin resistance in stable coronary artery disease patients measured by a point-of-care assay.
We studied 468 consecutive stable ...coronary artery disease patients in a referral cardiac center who were taking aspirin 80 to 325 mg daily for ≥4 weeks. The VerifyNow Aspirin (Ultegra RPFA-ASA, Accumetrics Inc, San Diego, Calif) was used to determine aspirin responsiveness. An aspirin reaction unit (ARU) ≥550 indicates the absence of aspirin-induced platelet dysfunction, based on correlation with epinephrine-induced light transmission aggregometry. Demographic and clinical data were collected to analyze the predictors of aspirin resistance.
Aspirin resistance was noted in 128 (27.4%) patients. Univariate predictors of aspirin resistance include elderly (
P = 0.002), women (
P <0.001), anemia (
P <0.001), renal insufficiency (
P = 0.009) and aspirin dose ≤100mg (
P = 0.004). Multivariate analysis revealed hemoglobin (odds ratio OR 0.6; 95% confidence interval CI 0.51 to 0.69;
P <0.001) and aspirin dose ≤100 mg (OR 2.23; 95% CI 1.12 to 4.44;
P = 0.022) to be independent predictors of aspirin resistance. Daily aspirin dose ≤ 100 mg was associated with increased prevalence of aspirin resistance compared with 150 mg and 300 mg daily (30.2% vs 16.7% vs 0%,
P = 0.0062).
A 100 mg or less daily dose of aspirin, which may have lower side effects, is associated with a higher incidence of aspirin resistance in patients with coronary artery disease. Prospective randomized studies are warranted to elucidate the optimal aspirin dosage for preventing ischemic complications of atherothrombotic disease.
Abstract
Background
Postoperative pneumocephalus is associated with a higher risk of recurrence of chronic subdural hematoma (cSDH). However, there is no verified simple way to measure the ...pneumocephalus volume at the bedside for daily clinical use. The ABC/2 method was shown to be a simple and reliable technique to estimate volumes of intracranial lesions, such as intracranial hematomas. This study aims to evaluate the accuracy of the ABC/2 formula in estimating volumes of pneumocephalus, as compared to the gold standard with computer-assisted volumetric analysis.
Methods
A total of 141 postoperative computed tomographic (CT) brain scans of cSDH patients with burr-hole drainage were analysed. Pneumocephalus volume was measured independently by both the ABC/2 formula and the computer-assisted volumetric measurement. For the computer-assisted measurement, the volume of the air was semiautomatically segmented and calculated by computer software. Linear regression was used to determine the correlation between the ABC/2 method and computer-assisted measurement.
Results
The postoperative pneumocephalus volume after bilateral burr-hole drainage was significantly larger than that of unilateral burr-hole drainage (29.34 ml versus 12.21 ml,
p
< 0.001). The estimated volumes by the formula ABC/2 significantly correlated to the volumes as measured by the computer-assisted volumetric technique, with
r
= 0.992 (
p
< 0.001). The Pearson correlation coefficient is very close to 1, which signifies a very strong positive correlation, and it is statistically significant.
Conclusions
An excellent correlation is observed between the ABC/2 method and the computer-assisted measurement. This study verified that the ABC/2 method is an accurate and simple “bedside” technique to estimate pneumocephalus volume.
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