The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a ...pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.
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•Two trivalent adenoviral-vectored COVID-19 vaccines were developed and evaluated•Intranasal, but not intramuscular, immunization induces tripartite mucosal immunity•Intranasal immunization protects against ancestral and variant strains of SARS-CoV-2•Optimal protection requires B and T cell immunity and trained innate immunity
Respiratory mucosal immunization with a next-generation adenoviral-vectored trivalent COVID-19 vaccine expressing spike, nucleocapsid, and RdRp antigens, induces all-around protective mucosal immunity against SARS-CoV-2 via induction of systemic and local antibodies, lung-tissue-resident memory T cells, and trained alveolar macrophages.
A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the ...precise relationship between BMI and all-cause mortality remains uncertain.
We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58).
The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval CI, 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up.
In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.
Abstract In humans, taurine (2-aminoethanesulfonic acid) is mainly obtained from diet. Despite the fact that the health effects of taurine are largely unknown, taurine has become a popular supplement ...and ingredient in energy drinks in recent years. Evidence from mechanistic and animal studies has shown that the main biological actions of taurine include its ability to conjugate bile acids, regulate blood pressure (BP), and act as a potent antioxidant and anti-inflammatory agent. These actions suggest that high levels of taurine may be protective against coronary heart disease (CHD). However, data from epidemiologic and intervention studies in humans are limited. We review what is known about taurine's metabolism, its transportation in the body, its food sources, and evidence of its effect on cardiovascular health from in vitro , animal, and epidemiologic studies. We also discuss shortcomings of the human studies that need to be addressed in the future. The identification of taurine as a preventive factor for CHD may be of great public health importance.
Summary Background Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and ...decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. Methods In this 2-year trial, patients aged 8–35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A1c (HbA1C ) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT00385697. Findings 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 99% in the teplizumab groups vs 98/99 99% in the placebo group) and serious adverse events (42/417 10% vs 9/99 9%). The most common clinical adverse event in the teplizumab groups was rash (220/417 53% vs 20/99 20% in the placebo group). Interpretation Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. Funding MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.
Work-related musculoskeletal disorders (WMSDs) have a significant impact on physical therapists, but few studies have addressed the issue. Research is needed to determine the scope of the problem and ...the effects of specific risk factors.
The objectives of this study were: (1) to determine the 1-year incidence rate of WMSDs in physical therapists and (2) to determine the effects of specific risk factors.
This was a prospective cohort study with 1-year follow-up.
Subjects were randomly selected American Physical Therapy Association members (N=882). Exposure assessment included demographic data, physical risk factors, job strain, and specific physical therapy tasks. The primary outcome was WMSDs, with a severity rating of at least 4/10 and present at least once a month or lasting longer than a week.
The response rate to the baseline questionnaire was 67%. Ninety-three percent of the subjects who responded to the baseline questionnaire responded to the follow-up questionnaire. The 1-year incidence rate of WMSDs was 20.7%. Factors that increased the risk for WMSDs included patient transfers, patient repositioning, bent or twisted postures, joint mobilization, soft tissue work, and job strain.
The primary limitation of this study was the number of therapists who had a change in their job situation during the follow-up year.
Work-related musculoskeletal disorders are prevalent in physical therapists. Physical therapy exposures, patient handling, and manual therapy, in particular, increase the risk for WMSDs.
Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone ...(AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.
In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.
The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.
AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.
In cohorts of 8-13, 53 participants were ...randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).
No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo,
= 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline,
= 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo,
= 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12,
= 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.
Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.
NCT02255422.
This study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes ...other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.
Large epidemiologic studies have the potential to make valuable contributions to the assessment of gene-environment interactions because they prospectively collected detailed exposure data. Some of ...these studies, however, have only serum or plasma samples as a low quantity source of DNA.
We examined whether DNA isolated from serum can be used to reliably and accurately genotype single nucleotide polymorphisms (SNPs) using Sequenom multiplex SNP genotyping technology. We genotyped 81 SNPs using samples from 158 participants in the NYU Women's Health Study. Each participant had DNA from serum and at least one paired DNA sample isolated from a high quality source of DNA, i.e. clots and/or cell precipitates, for comparison.
We observed that 60 of the 81 SNPs (74%) had high call frequencies (≥95%) using DNA from serum, only slightly lower than the 85% of SNPs with high call frequencies in DNA from clots or cell precipitates. Of the 57 SNPs with high call frequencies for serum, clot, and cell precipitate DNA, 54 (95%) had highly concordant (>98%) genotype calls across all three sample types. High purity was not a critical factor to successful genotyping.
Our results suggest that this multiplex SNP genotyping method can be used reliably on DNA from serum in large-scale epidemiologic studies.
Living in neighborhoods with higher levels of walkability has been associated with a reduced risk of obesity and higher levels of physical activity. Obesity has been linked to increased risk of 13 ...cancers in women. However, long-term prospective studies of neighborhood walkability and risk for obesity-related cancer are scarce.
We evaluated the association between long-term average neighborhood walkability and obesity-related cancer risk in women.
The New York University Women's Health Study (NYUWHS) is a prospective cohort with 14,274 women recruited between 1985 and 1991 in New York City and followed over nearly three decades. We geocoded residential addresses for each participant throughout follow-up and calculated an average annual measure of neighborhood walkability across years of follow-up using data on population density and accessibility to destinations associated with geocoded residential addresses. We used ICD-9 codes to characterize first primary obesity-related cancers and employed Cox proportional hazards models to assess the association between average neighborhood walkability and risk of overall and site-specific obesity-related cancers.
Residing in neighborhoods with a higher walkability level was associated with a reduced risk of overall and site-specific obesity-related cancers. The hazards ratios associated with a 1-standard deviation increase in average annual neighborhood walkability were 0.88 (95% CI: 0.85, 0.93) for overall obesity-related cancer, 0.89 (95% CI: 0.84, 0.95) for postmenopausal breast cancer, 0.82 (95% CI: 0.68, 0.99) for ovarian cancer, 0.87 (95% CI: 0.76, 0.99) for endometrial cancer, and 0.68 (95% CI: 0.49, 0.94) for multiple myeloma, adjusting for potential confounders at both the individual and neighborhood level. The association between neighborhood walkability and risk of overall obesity-related cancer was stronger among women living in neighborhoods with higher levels of poverty compared with women living in areas with lower poverty levels (
).
Our study highlights a potential protective role of neighborhood walkability in preventing obesity-related cancers in women. https://doi.org/10.1289/EHP11538.
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