Knowing whether COVID-19 vaccine effectiveness wanes is crucial for informing vaccine policy, such as the need for and timing of booster doses. We aimed to systematically review the evidence for the ...duration of protection of COVID-19 vaccines against various clinical outcomes, and to assess changes in the rates of breakthrough infection caused by the delta variant with increasing time since vaccination.
This study was designed as a systematic review and meta-regression. We did a systematic review of preprint and peer-reviewed published article databases from June 17, 2021, to Dec 2, 2021. Randomised controlled trials of COVID-19 vaccine efficacy and observational studies of COVID-19 vaccine effectiveness were eligible. Studies with vaccine efficacy or effectiveness estimates at discrete time intervals of people who had received full vaccination and that met predefined screening criteria underwent full-text review. We used random-effects meta-regression to estimate the average change in vaccine efficacy or effectiveness 1–6 months after full vaccination.
Of 13 744 studies screened, 310 underwent full-text review, and 18 studies were included (all studies were carried out before the omicron variant began to circulate widely). Risk of bias, established using the risk of bias 2 tool for randomised controlled trials or the risk of bias in non-randomised studies of interventions tool was low for three studies, moderate for eight studies, and serious for seven studies. We included 78 vaccine-specific vaccine efficacy or effectiveness evaluations (Pfizer–BioNTech-Comirnaty, n=38; Moderna-mRNA-1273, n=23; Janssen-Ad26.COV2.S, n=9; and AstraZeneca-Vaxzevria, n=8). On average, vaccine efficacy or effectiveness against SARS-CoV-2 infection decreased from 1 month to 6 months after full vaccination by 21·0 percentage points (95% CI 13·9–29·8) among people of all ages and 20·7 percentage points (10·2–36·6) among older people (as defined by each study, who were at least 50 years old). For symptomatic COVID-19 disease, vaccine efficacy or effectiveness decreased by 24·9 percentage points (95% CI 13·4–41·6) in people of all ages and 32·0 percentage points (11·0–69·0) in older people. For severe COVID-19 disease, vaccine efficacy or effectiveness decreased by 10·0 percentage points (95% CI 6·1–15·4) in people of all ages and 9·5 percentage points (5·7–14·6) in older people. Most (81%) vaccine efficacy or effectiveness estimates against severe disease remained greater than 70% over time.
COVID-19 vaccine efficacy or effectiveness against severe disease remained high, although it did decrease somewhat by 6 months after full vaccination. By contrast, vaccine efficacy or effectiveness against infection and symptomatic disease decreased approximately 20–30 percentage points by 6 months. The decrease in vaccine efficacy or effectiveness is likely caused by, at least in part, waning immunity, although an effect of bias cannot be ruled out. Evaluating vaccine efficacy or effectiveness beyond 6 months will be crucial for updating COVID-19 vaccine policy.
Coalition for Epidemic Preparedness Innovations.
Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and ...NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways. To better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines that further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.
Historical ecology has revolutionized our understanding of fisheries and cultural landscapes, demonstrating the value of historical data for evaluating the past, present, and future of Earth's ...ecosystems. Despite several important studies, Indigenous fisheries generally receive less attention from scholars and managers than the 17th-20th century capitalist commercial fisheries that decimated many keystone species, including oysters. We investigate Indigenous oyster harvest through time in North America and Australia, placing these data in the context of sea level histories and historical catch records. Indigenous oyster fisheries were pervasive across space and through time, persisting for 5000-10,000 years or more. Oysters were likely managed and sometimes "farmed," and are woven into broader cultural, ritual, and social traditions. Effective stewardship of oyster reefs and other marine fisheries around the world must center Indigenous histories and include Indigenous community members to co-develop more inclusive, just, and successful strategies for restoration, harvest, and management.
Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of ...routinely prescribed chemotherapy drugs are poorly understood.
We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was assessed by qRT-PCR, copy number, western blotting and immunohistochemical analysis and ABCB1 activity assessed by the Vybrant and P-glycoprotein-Glo assays.
Paclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib but not to veliparib or AZD2461. Resistance correlated with increased ABCB1 expression and was reversible following treatment with the ABCB1 inhibitors verapamil and elacridar. Active efflux of paclitaxel, olaparib, doxorubicin and rucaparib was confirmed in drug-resistant cells and in ABCB1-expressing bacterial membranes.
We describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. Optimal choice of PARP inhibitor may therefore limit the progression of drug-resistant disease, while routine prescription of first-line paclitaxel may significantly limit subsequent chemotherapy options in ovarian cancer patients.
Abstract Dental tissue infection and disease result in acute and chronic activation of the innate immune response, which is mediated by molecular and cellular signaling. Different cell types within ...the dentin-pulp complex are able to detect invading bacteria at all stages of the infection. Indeed, at relatively early disease stages, odontoblasts will respond to bacterial components, and as the disease progresses, core pulpal cells including fibroblasts, stems cells, endothelial cells, and immune cells will become involved. Pattern recognition receptors, such as Toll-like receptors expressed on these cell types, are responsible for detecting bacterial components, and their ligand binding leads to the activation of the nuclear factor-kappa B and p38 mitogen-activated protein (MAP) kinase intracellular signaling cascades. Subsequent nuclear translocation of the transcription factor subunits from these pathways will lead to proinflammatory mediator expression, including increases in cytokines and chemokines, which trigger host cellular defense mechanisms. The complex molecular signaling will result in the recruitment of immune system cells targeted at combating the invading microbes; however, the trafficking and antibacterial activity of these cells can lead to collateral tissue damage. Recent evidence suggests that if inflammation is resolved relatively low levels of proinflammatory mediators may promote tissue repair, whereas if chronic inflammation ensues repair mechanisms become inhibited. Thus, the effects of mediators are temporal context dependent. Although containment and removal of the infection are keys to enable dental tissue repair, it is feasible that the development of anti-inflammatory and immunomodulatory approaches, based on molecular, epigenetic, and photobiomodulatory technologies, may also be beneficial for future endodontic treatments.
Poorly designed labels and packaging are key contributors to medication errors. To identify attributes of labels and dosing tools that could be improved, we examined the extent to which dosing error ...rates are affected by tool characteristics (ie, type, marking complexity) and discordance between units of measurement on labels and dosing tools; along with differences by health literacy and language.
Randomized controlled experiment in 3 urban pediatric clinics. English- or Spanish-speaking parents (n = 2110) of children ≤8 years old were randomly assigned to 1 of 5 study arms and given labels and dosing tools that varied in unit pairings. Each parent measured 9 doses of medication (3 amounts 2.5, 5, and 7.5 mL and 3 tools 1 cup, 2 syringes (0.2- and 0.5-mL increments)), in random order. Outcome assessed was dosing error (>20% deviation; large error defined as > 2 times the dose).
A total of 84.4% of parents made ≥1 dosing error (21.0% ≥1 large error). More errors were seen with cups than syringes (adjusted odds ratio = 4.6; 95% confidence interval, 4.2-5.1) across health literacy and language groups (P < .001 for interactions), especially for smaller doses. No differences in error rates were seen between the 2 syringe types. Use of a teaspoon-only label (with a milliliter and teaspoon tool) was associated with more errors than when milliliter-only labels and tools were used (adjusted odds ratio = 1.2; 95% confidence interval, 1.01-1.4).
Recommending oral syringes over cups, particularly for smaller doses, should be part of a comprehensive pediatric labeling and dosing strategy to reduce medication errors.
This collection examines young adult Gothic fiction to demonstrate how the contemporary resurgence of the Gothic in texts for young people signals anxieties about, and hopes for, young people in the ...twenty-first century.
Abstract Background Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimer’s disease (AD). The purpose of this study was to examine serum antibody ...levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects. Methods Serum samples from 158 participants in the Biologically Resilient Adults in Neurological Studies research program at the University of Kentucky were analyzed for immunoglobulin G antibody levels to seven oral bacteria associated with periodontitis, including Aggregatibacter actinomycetemcomitans , Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum , Tannerella forsythia, and Prevotella intermedia . All 158 participants were cognitively intact at baseline venous blood draw. In all, 81 of the participants developed either mild cognitive impairment (MCI) or AD or both, and 77 controls remained cognitively intact in the years of follow-up. Antibody levels were compared between controls and subjects with AD at baseline draw and after conversion and controls and subjects with MCI at baseline draw and after conversion using the Wilcoxon rank-sum test. AD and MCI participants were not directly compared. Linear regression models were used to adjust for potential confounding. Results Antibody levels to F nucleatum and P intermedia were significantly increased (α = 0.05) at baseline serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status. Conclusions This study provides initial data that demonstrate elevated antibodies to periodontal disease bacteria in subjects years before cognitive impairment and suggests that periodontal disease could potentially contribute to the risk of AD onset/progression. Additional cohort studies profiling oral clinical presentation with systemic response and AD and prospective studies to evaluate any cause-and-effect association are warranted.
Abstract
Background
Ovarian cancer patients frequently develop chemotherapy resistance, limiting treatment options. We have previously shown that individuality in fibroblast growth factor 1 (
FGF1
) ...expression influences survival and chemotherapy response.
Methods
We used MTT assays to assess chemosensitivity to cisplatin and carboplatin following shRNA-mediated knockdown or heterologous over-expression of FGF1 (quantified by qRT-PCR and immunoblot analysis), and in combination with the FGFR inhibitors AZD4547 and SU5402, the ATM inhibitor KU55933 and DNA-PK inhibitor NU7026. Immunofluorescence microscopy was used to quantify the FGF1-dependent timecourse of replication protein A (RPA) and γH2AX foci formation.
Results
Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7026 re-sensitised resistant cells. FGF1 expression influenced the timecourse of damage-induced RPA and γH2AX nuclear foci formation.
Conclusion
Drug resistance arises from FGF1-mediated differential activation of high-fidelity homologous recombination DNA damage repair. FGFR and ATM inhibitors reverse platinum drug resistance, highlighting novel combination chemotherapy approaches for future clinical trial evaluation.
Accounting for more than 60% of cancer survivors, older (≥65 years) cancer survivors have a 2- to 5-fold risk of physical function impairment, compared to cancer-free peers. One strategy to improve ...physical function is dietary and resistance training interventions, which improve muscle strength and mass by stimulating muscle protein synthesis. The E-PROOF (E-intervention for Protein Intake and Resistance Training to Optimize Function) study will examine the feasibility, acceptability, and preliminary efficacy of a 12-week randomized controlled trial of an online, tailored nutritional and resistance training education and counseling intervention to improve physical function and associated health outcomes (muscle strength, health-related quality of life (HRQoL), self-efficacy, and weight management).
In this study, 70 older cancer survivors will be randomized to one of two groups: experimental (receiving remote behavioral counseling and evidence-based education and resources), and control (general survivorship education). We will examine the intervention effects on physical function, muscle strength, HRQoL, self-efficacy, weight, and waist circumference during a 12-week period between the experimental and control groups. Three months following the end of the intervention, we will conduct a follow-up assessment to measure physical function, muscle strength, and HRQoL.
This study is the first synchronous, online protein-focused diet and resistance training intervention among older cancer survivors. This novel study advances science by promoting independent health behaviors among older cancer survivors to improve health outcomes, and provide foundational knowledge to further address this growing problem on a wider scale through online platforms.
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