SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms ...underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with a 382-nucleotide deletion (∆382) in the open reading frame 8 (ORF8) region of the genome have been detected in Singapore and ...other countries. We investigated the effect of this deletion on the clinical features of infection.
We retrospectively identified patients who had been screened for the ∆382 variant and recruited to the PROTECT study—a prospective observational cohort study conducted at seven public hospitals in Singapore. We collected clinical, laboratory, and radiological data from patients' electronic medical records and serial blood and respiratory samples taken during hospitalisation and after discharge. Individuals infected with the ∆382 variant were compared with those infected with wild-type SARS-CoV-2. Exact logistic regression was used to examine the association between the infection groups and the development of hypoxia requiring supplemental oxygen (an indicator of severe COVID-19, the primary endpoint). Follow-up for the study's primary endpoint is completed.
Between Jan 22 and March 21, 2020, 278 patients with PCR-confirmed SARS-CoV-2 infection were screened for the ∆382 deletion and 131 were enrolled onto the study, of whom 92 (70%) were infected with the wild-type virus, ten (8%) had a mix of wild-type and ∆382-variant viruses, and 29 (22%) had only the ∆382 variant. Development of hypoxia requiring supplemental oxygen was less frequent in the ∆382 variant group (0 0% of 29 patients) than in the wild-type only group (26 28% of 92; absolute difference 28% 95% CI 14–28). After adjusting for age and presence of comorbidities, infection with the ∆382 variant only was associated with lower odds of developing hypoxia requiring supplemental oxygen (adjusted odds ratio 0·07 95% CI 0·00–0·48) compared with infection with wild-type virus only.
The ∆382 variant of SARS-CoV-2 seems to be associated with a milder infection. The observed clinical effects of deletions in ORF8 could have implications for the development of treatments and vaccines.
National Medical Research Council Singapore.
Doppler wind LiDAR (Light Detection And Ranging) makes use of the principle of optical Doppler shift between the reference and backscattered radiations to measure radial velocities at distances up to ...several kilometers above the ground. Such instruments promise some advantages, including its large scan volume, movability and provision of 3-dimensional wind measurements, as well as its relatively higher temporal and spatial resolution comparing with other measurement devices. In recent decades, Doppler LiDARs developed by scientific institutes and commercial companies have been well adopted in several real-life applications. Doppler LiDARs are installed in about a dozen airports to study aircraft-induced vortices and detect wind shears. In the wind energy industry, the Doppler LiDAR technique provides a promising alternative to in-situ techniques in wind energy assessment, turbine wake analysis and turbine control. Doppler LiDARs have also been applied in meteorological studies, such as observing boundary layers and tracking tropical cyclones. These applications demonstrate the capability of Doppler LiDARs for measuring backscatter coefficients and wind profiles. In addition, Doppler LiDAR measurements show considerable potential for validating and improving numerical models. It is expected that future development of the Doppler LiDAR technique and data processing algorithms will provide accurate measurements with high spatial and temporal resolutions under different environmental conditions.
Objective
The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease ...has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial DNA (mtDNA) rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA.
Methods
Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the midyear period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondrial diseases.
Results
The minimum prevalence rate for mtDNA mutations was 1 in 5,000 (20 per 100,000), comparable with our previously published prevalence rates. In this population, nuclear mutations were responsible for clinically overt adult mitochondrial disease in 2.9 per 100,000 adults.
Interpretation
Combined, our data confirm that the total prevalence of adult mitochondrial disease, including pathogenic mutations of both the mitochondrial and nuclear genomes (≈1 in 4,300), is among the commonest adult forms of inherited neurological disorders. These figures hold important implications for the evaluation of interventions, provision of evidence‐based health policies, and planning of future services. Ann Neurol 2015 Ann Neurol 2015;77:753–759
Summary Background Guidelines on pain management recommend that patients at risk of ulcers receive either a cyclo-oxygenase (COX 2) inhibitor or a non-steroidal anti-inflammatory drug (NSAID) with a ...proton-pump inhibitor (PPI). These two treatments have similar effectiveness, but they are insufficient for protection of patients at very high risk for ulcer bleeding. We aimed to test the hypothesis that in patients with previous ulcer bleeding induced by non-selective NSAIDs, combined treatment with the COX 2 inhibitor celecoxib and the PPI esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding. Methods 441 consecutively presenting patients who were taking non-selective NSAIDs for arthritis were recruited to our single-centre, prospective, randomised, double-blind trial after admission to hospital with upper-gastrointestinal bleeding. Patients were enrolled after their ulcers had healed and a histological test for Helicobacter pylori was negative. All patients were given 200 mg celecoxib twice daily. 137 patients were randomly assigned to receive 20 mg esomeprazole twice daily (combined-treatment group), and 136 to receive a placebo (control group) for 12 months. The primary endpoint was recurrent ulcer bleeding during treatment or within 1 month of the end of treatment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00365313. Findings Combination treatment was more effective than celecoxib alone for prevention of ulcer bleeding in patients at high risk. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8·9%) in the controls (95% CI difference, 4·1 to 13·7; p=0·0004). The median follow-up was 13 months (range 0·4–13·0). Discontinuation of treatment and the incidence of adverse events were similar in the two treatment groups. Interpretation Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.
Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple ...compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants.
Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker ...of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.
A patient with nasopharyngeal carcinoma (NPC) treated by radiotherapy developed tension pneumocephalus due to a naso-cranial fistula. The fistula was due to a pathological fracture at the base of ...skull affected by bone necrosis. The clinical features, neuro-radiological and post-mortem findings are presented. This is the first case report of pneumocephalus in association with NPC. The brain showed florid subarachnoid and intraventricular air collection under tension, low grade meningitis, foreign body giant cell reaction in the arachnoid membrane and multifocal cerebral infarction. Late radiation necrosis was also found in the left temporal lobe. The cause of the tension pneumocephalus in relation to radiation bone necrosis and the possible role of pneumocephalus in producing the multifocal cerebral infarction are discussed. The more common radiation necrosis of brain is also discussed. The pathogenesis of the pneumocephalus in this patient is distinctly different from the more common causes such as head injury and surgery.
Background
Various strategies of weaning V‐A ECMO have been described. PCRTO is a weaning technique which involves serial decremental pump revolutions until a retrograde flow from the arterial to ...venous ECMO cannula is achieved. It has been reported as a feasible weaning strategy in the pediatric population, but its application in adults has not been widely reported.
Methods
This was a case series including all adult patients who underwent PCRTO during weaning from V‐A ECMO at a tertiary ECMO center between January 2019 and July 2021. The primary end point was the successful weaning from V‐A ECMO support.
Results
A total of 57 runs of PCRTO in 36 patients were analyzed—45 (78.9%) of the trials were concluded successfully. The median retrograde blood flow rate during PCRTO was 0.6 ± 0.2 L/min, and the median duration of each PCRTO was 180 (120–240) min. Of the 35 patients who had at least one session of successful PCRTO, 31 (88.6%) were ultimately weaned from ECMO. There were no major complications from PCRTO including systemic or circuit thrombosis.
Conclusions
PCRTO is a feasible strategy for assessing readiness for weaning from V‐A ECMO with a low risk of adverse events and high rate of predicting eventual successful ECMO decannulation. Further investigation including comparison with alternative weaning strategies in prospective studies is required to confirm the approach.
•Regular surveillance monitoring is needed for early detection of local recurrence.•Surgery should be considered whenever feasible due to its lower complication risk.•The therapeutic margin in ...re-irradiation is narrow.•Most common fatal radiotherapy toxicities include mucosal necrosis and haemorrhage.•Role of systemic treatment is unclear, may only be chosen in conservative settings.
As a consequence of the current excellent loco-regional control rates attained using the generally accepted treatment paradigms involving intensity-modulated radiotherapy for nasopharyngeal carcinoma (NPC), only 10–20% of patients will suffer from local and/or nodal recurrence after primary treatment. Early detection of recurrence is important as localized recurrent disease is still potentially salvageable, but this treatment often incurs a high risk of major toxicities. Due to the possibility of radio-resistance of tumors which persist or recur despite adequate prior irradiation and the limited tolerance of adjacent normal tissues to sustain further additional treatment, the management of local failures remains one of the greatest challenges in this disease. Both surgical approaches for radical resection and specialized re-irradiation modalities have been explored. Unfortunately, available data are based on retrospective studies, and the majority of them are based on a small number of patients or relatively short follow-up. In this article, we will review the different salvage treatment options and associated prognostic factors for each of them. We will also propose a treatment algorithm based on the latest available evidence and discuss the future directions of treatment for locally recurrent NPC.
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