Haematology and biochemistry safety monitoring blood results are also reported from the immunology cohort (100 participants with additional visits), at baseline (before the prime dose), at day 28 ...(before the boost dose) and 7 days post-boost, graded according to a modified US Food and Drug Administration toxicity scale (appendix). In this interim safety analysis, we found an increase in systemic reactogenicity after the boost dose reported by participants in heterologous vaccine schedules in comparison to homologous vaccine schedules, and this was accompanied by increased paracetamol usage. Of note, these data were obtained in participants aged 50 years and older, and reactogenicity might be higher in younger age groups4,5 for whom a mixed vaccination schedule is being advocated in Germany, France, Sweden, Norway, and Denmark among those who have received a ChAd prime dose, in light of concerns regarding thrombotic thrombocytopenia after the first dose of ChAd.6 Pending availability of a more complete safety dataset and immunogenicity results for heterologous prime-boost schedules (to be reported shortly), these data suggest that the two heterologous vaccine schedules in this trial might have some short-term disadvantages.
Nosocomial spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been widely reported, but the transmission pathways among patients and healthcare workers (HCWs) are unclear. ...Identifying the risk factors and drivers for these nosocomial transmissions is critical for infection prevention and control interventions. The main aim of our study was to quantify the relative importance of different transmission pathways of SARS-CoV-2 in the hospital setting.
This is an observational cohort study using data from 4 teaching hospitals in Oxfordshire, United Kingdom, from January to October 2020. Associations between infectious SARS-CoV-2 individuals and infection risk were quantified using logistic, generalised additive and linear mixed models. Cases were classified as community- or hospital-acquired using likely incubation periods of 3 to 7 days. Of 66,184 patients who were hospitalised during the study period, 920 had a positive SARS-CoV-2 PCR test within the same period (1.4%). The mean age was 67.9 (±20.7) years, 49.2% were females, and 68.5% were from the white ethnic group. Out of these, 571 patients had their first positive PCR tests while hospitalised (62.1%), and 97 of these occurred at least 7 days after admission (10.5%). Among the 5,596 HCWs, 615 (11.0%) tested positive during the study period using PCR or serological tests. The mean age was 39.5 (±11.1) years, 78.9% were females, and 49.8% were nurses. For susceptible patients, 1 day in the same ward with another patient with hospital-acquired SARS-CoV-2 was associated with an additional 7.5 infections per 1,000 susceptible patients (95% credible interval (CrI) 5.5 to 9.5/1,000 susceptible patients/day) per day. Exposure to an infectious patient with community-acquired Coronavirus Disease 2019 (COVID-19) or to an infectious HCW was associated with substantially lower infection risks (2.0/1,000 susceptible patients/day, 95% CrI 1.6 to 2.2). As for HCW infections, exposure to an infectious patient with hospital-acquired SARS-CoV-2 or to an infectious HCW were both associated with an additional 0.8 infection per 1,000 susceptible HCWs per day (95% CrI 0.3 to 1.6 and 0.6 to 1.0, respectively). Exposure to an infectious patient with community-acquired SARS-CoV-2 was associated with less than half this risk (0.2/1,000 susceptible HCWs/day, 95% CrI 0.2 to 0.2). These assumptions were tested in sensitivity analysis, which showed broadly similar results. The main limitations were that the symptom onset dates and HCW absence days were not available.
In this study, we observed that exposure to patients with hospital-acquired SARS-CoV-2 is associated with a substantial infection risk to both HCWs and other hospitalised patients. Infection control measures to limit nosocomial transmission must be optimised to protect both staff and patients from SARS-CoV-2 infection.
The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, ...and-selectively-with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT).
ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for
fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles.
The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade (
= .0044) but not by age, location,
fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% 95% CI, 74.4% to 91.2%
47.4% 95% CI, 26.0% to 68.8%;
= .0013).
The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.
Perioperative malnutrition has proven to be challenging to define, diagnose, and treat. Despite these challenges, it is well known that suboptimal nutritional status is a strong independent predictor ...of poor postoperative outcomes. Although perioperative caregivers consistently express recognition of the importance of nutrition screening and optimization in the perioperative period, implementation of evidence-based perioperative nutrition guidelines and pathways in the United States has been quite limited and needs to be addressed in surgery-focused recommendations. The second Perioperative Quality Initiative brought together a group of international experts with the objective of providing consensus recommendations on this important topic with the goal of (1) developing guidelines for screening of nutritional status to identify patients at risk for adverse outcomes due to malnutrition; (2) address optimal methods of providing nutritional support and optimizing nutrition status preoperatively; and (3) identifying when and how to optimize nutrition delivery in the postoperative period. Discussion led to strong recommendations for implementation of routine preoperative nutrition screening to identify patients in need of preoperative nutrition optimization. Postoperatively, nutrition delivery should be restarted immediately after surgery. The key role of oral nutrition supplements, enteral nutrition, and parenteral nutrition (implemented in that order) in most perioperative patients was advocated for with protein delivery being more important than total calorie delivery. Finally, the role of often-inadequate nutrition intake in the posthospital setting was discussed, and the role of postdischarge oral nutrition supplements was emphasized.
According to WHO, SARS-CoV-2 is estimated to have caused 265 million infections and more than 5 million deaths over the past 2 years. First alpha and then delta variants spread globally causing ...successive waves of infection, while large localised outbreaks were caused in southern Africa by the beta variant and in South America by the gamma variant. Omicron contains a large number of mutations in S compared with previous variants of concern, mostly concentrated around the receptor binding motif: 30 amino acid substitutions, deletion of six residues, and insertion of three residues.1 Mutations are also present at other sites (receptor binding domain and N-terminal domain) which might affect neutralising antibodies.
CONTEXT Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis. OBJECTIVE To assess the association ...between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease. DESIGN, SETTING, AND PATIENTS An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n = 3165) or DES (n = 1501). Landmark analyses were performed among patients who were event-free (no death, myocardial infarction MI, or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. MAIN OUTCOME MEASURES Death, nonfatal MI, and the composite of death or MI at 24-month follow-up. RESULTS Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, −3.3%; 95% CI, −6.3% to −0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, −4.1%; 95% CI, −7.6% to −0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, −0.7%; 95% CI, −2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, −0.5%; 95% CI, −3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, −3.5%; 95% CI, −5.9% to −1.1%; P = .004) and death or MI (0% vs 4.5%; difference, −4.5%; 95% CI, −7.1% to −1.9%; P<.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, −1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, −1.6% to 3.6%; P = .44). CONCLUSIONS The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial.Published online December 5, 2006 (doi:10.1001/jama.297.2.joc60179).
Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family ...members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
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•Mutations in tubulin, alpha 4A (TUBA4A) are associated with familial ALS•TUBA4A mutants act as dominant negatives to alter microtubule dynamics and stability•Results provide further evidence supporting a role of cytoskeletal defects in ALS•Rare variant analysis of index familial cases can identify human disease genes
Smith et al. show that alterations in the Tubulin, Alpha 4A gene, which encodes a cytoskeletal protein, contribute to the pathogenesis of familial ALS. This Report provides further evidence supporting a major role of cytoskeletal defects in ALS.
Objective
Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP‐43 inclusions have been found in both ALS ...and FTD cases (FTD‐TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS‐FTD.
Methods
We used published genome‐wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology‐proven FTD‐TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta‐analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD‐TDP sample sizes.
Results
Meta‐analysis identified 19 genome‐wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10−12) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10−11) as shared susceptibility loci for ALS and FTD‐TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10−7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10−7).
Interpretation
We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD‐TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD‐TDP. Ann Neurol 2014;76:120–133
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the
gene in 13 ...individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (
= 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing
with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in
are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
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