Recognizing both the medical and operational costs of tobacco use, the Department of Defense has made tobacco cessation a top health promotion priority. Military tobacco rates remain high, however, ...especially among younger personnel and, particularly, in the Marine Corps. Tobacco is prohibited during basic training, but relapse is common following boot camp graduation. The objective of this study was to determine patterns and prevalence of tobacco use among Marine Corps recruits before entering basic training. Over a period of 14 months, 15,689 graduating male recruits completed a survey of their preservice tobacco use. Approximately 81% reported having tried tobacco at least once and 57% were classified as at-risk users. Compared to their civilian peers, more recruits were daily users and many more used smokeless tobacco. Approximately 67% of users evidenced at least one indicator of dependence. There is a clear need for additional tobacco cessation efforts to target this high-risk population.
This study evaluated the overall effectiveness of the Navy's three-tiered obesity treatment program and compared effectiveness across the three treatment levels. Height, weight, and body ...circumference measurements were obtained from 369 program participants at baseline and follow-up (6 weeks, 6 months, 12 months). Results demonstrated a significant and sustained reduction in percent body fat in all three program tiers, but the absolute losses at the end of 12 months were small: -3.7% fat for men, -4.5% fat for women. The level III tier, which employs a multidimensional approach to treatment, was the most effective program, even after differences in enrollees' initial percent body fat were taken into account. Changes in the approach to treatment and development of a supportive, long-term, behaviorally based aftercare program are recommended.
This study examines long-term health and physical readiness trends in the U.S. Navy. We mailed lifestyle questionnaires to all participants in baseline studies between 1983 and 1989 who were still on ...active duty in 1994. Commands provided body composition and physical readiness test scores for the participants. Two longitudinal cohorts were created: an 8-year sample (N = 640) with matched data from 1986, 1989, and 1994; and an 11-year sample (N = 1,576), with data from 1983 and 1994. Analyses of both cohorts revealed significant improvements in cardiovascular fitness, muscle strength, exercise, lean body mass, dietary habits, and sleep, as well as significant decreases in tobacco and alcohol use and job stress. However, hypertension rates, percentage of body fat, and body mass index increased over time. Women's scores were significantly better than men's on a number of factors. Overall, these findings suggest that the Navy's health promotion efforts have had a significant positive effect on the fitness and health behaviors of career Navy men and women.
Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus disease 2019 (COVID-19) vaccination has important public health implications in the decision ...to vaccinate youth.
We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions.
We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable) at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median age was 15.8 years (range, 12.1-20.3; interquartile range IQR, 14.5-17.0). Suspected myocarditis occurred in 136 patients (97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second dose. Symptoms started at a median of 2 days (range, 0-22; IQR, 1-3) after vaccination. The most common symptom was chest pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation or died. Median hospital stay was 2 days (range, 0-10; IQR, 2-3). All patients had elevated troponin I (n=111, 8.12 ng/mL; IQR, 3.50-15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25-1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent cardiac MRI at a median 5 days (range, 0-88; IQR, 3-17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25).
Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate risk factors, mechanisms, and long-term outcomes.
There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, ...and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.
Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test).
Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development.
http://www.ClinicalTrials.gov (#NCT00047073).
Gene activation in metazoans is accompanied by the presence of histone variants H2AZ and H3.3 within promoters and enhancers. It is not known, however, what protein deposits H3.3 into chromatin or ...whether variant chromatin plays a direct role in gene activation. Here we show that chromatin containing acetylated H2AZ and H3.3 stimulates transcription in vitro. Analysis of the Pol II pre-initiation complex on immobilized chromatin templates revealed that the E1A binding protein p400 (EP400) was bound preferentially to and required for transcription stimulation by acetylated double-variant chromatin. EP400 also stimulated H2AZ/H3.3 deposition into promoters and enhancers and influenced transcription in vivo at a step downstream of the Mediator complex. EP400 efficiently exchanged recombinant histones H2A and H3.1 with H2AZ and H3.3, respectively, in a chromatin- and ATP-stimulated manner in vitro. Our data reveal that EP400 deposits H3.3 into chromatin alongside H2AZ and contributes to gene regulation after PIC assembly.
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•Double-variant H2AZ-H3.3-containing chromatin stimulates transcription in vitro•EP400 contributes to gene activation in vivo and in vitro•EP400 is necessary for H2AZ and H3.3 deposition into enhancers and promoters in vivo•Purified EP400 exchanges both H2AZ and H3.3 into canonical chromatin in vitro
Deposition of the histone variants H2AZ and H3.3 accompanies gene transcription in metazoans. Pradhan et al. show that EP400 contributes to transcription on variant chromatin in vitro and that EP400 knockdown reduces deposition of H2AZ and H3.3 into promoters and enhancers and decreases gene expression in vivo.
To examine relationships amongst parental post-traumatic stress symptoms, parental post-traumatic growth, overprotective parenting, and child emotional/behavioural problems in families of children ...with critical CHD.
Sixty parents (15 fathers) of children aged 1-6 completed online questionnaires assessing parental post-traumatic stress symptoms and post-traumatic growth, overprotective parenting, and child emotional/behavioural problems. Bivariate correlations and mediational analyses were conducted to evaluate overprotective parenting as a mediator of the association between parental post-traumatic stress symptoms and child emotional/behavioural problems.
Parents reported significant post-traumatic stress symptoms, with over 18% meeting criteria for post-traumatic stress disorder and 70% meeting criteria in one or more clusters. Parental post-traumatic growth was positively correlated with intrusion (r = .32, p = .01) but it was not associated with other post-traumatic stress symptom clusters. Parental post-traumatic stress symptoms were positively associated with overprotective parenting (r = .37, p = .008) and total child emotional/behavioural problems (r = .29, p = .037). Overprotective parenting was positively associated with total child emotional/behavioural problems (r = .45, p = .001) and fully mediated the relationship between parental post-traumatic stress symptoms and child emotional/behavioural problems.
Overprotective parenting mediates the relationship between parental post-traumatic stress symptoms and child emotional and behavioural problems in families of children with CHD. Both parental post-traumatic stress symptoms and overprotective parenting may be modifiable risk factors for poor child outcomes. This study highlights the need for interventions to prevent or reduce parental post-traumatic stress symptoms and to promote effective parenting following a diagnosis of CHD.
So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, ...and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.
The Gene Ontology (GO) project (http://www.geneontology.org/) provides a set of structured, controlled vocabularies for community use in annotating genes, gene products and sequences (also see ...http://www.sequenceontology.org/). The ontologies have been extended and refined for several biological areas, and improvements to the structure of the ontologies have been implemented. To improve the quantity and quality of gene product annotations available from its public repository, the GO Consortium has launched a focused effort to provide comprehensive and detailed annotation of orthologous genes across a number of ‘reference’ genomes, including human and several key model organisms. Software developments include two releases of the ontology-editing tool OBO-Edit, and improvements to the AmiGO browser interface.
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