Early onset breast cancer is the most common malignancy in women with Li‐Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 ...carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53‐specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.
This article presents a review of published studies and analysis of age‐level data from individuals undergoing multigene panel testing and confirms that HER2+ breast tumor status is overrepresented patients with TP53 pathogenic variants, in particular patients with early onset cancer. This study also proposes a strategy to use this information within ACMG/AMP guidelines as evidence toward TP53 variant pathogenicity.
We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new ...consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.
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•Proteogenomics provides new insights into oncogenic signaling in endometrial carcinoma•Global acetylome and phosphoproteome surveys identify new regulatory mechanisms•QKI, circRNAs, and miRNAs form a potential feedback loop to promote EMT•Antigen presentation defects may render MSI tumors resistant to checkpoint blockade
Proteogenomic analyses of prospectively collected endometrial carcinomas provide insights into the role of underlying molecular pathways and the immune landscape that drive disease.
To describe a novel early vocational rehabilitation programme (In-Voc) for inpatients with spinal cord injury and to report early vocational outcomes.
Observational longitudinal cohort study.
One ...hundred adults with spinal cord injury admitted to spinal units in Sydney, Australia within a 24-month period.
In-Voc was offered to all inpatients within the first 6 months of acquired spinal cord injury and was provided by trained vocational consultants. Baseline demographics, opinions about work readiness, details of the vocational services provided and preliminary employment outcomes were documented.
The In-Voc programme was relatively short in duration (median 11 weeks, range 3-39 weeks) with a median total of 9.1 h (range 1-75.2 h) of service delivered per participant. At case closure (median 3 weeks post-discharge), 29/84 (34.5%) of participants were in paid employment (7% full-time, 8% part-time, 7% on sick leave, and 12% working with hours unknown), 36% were unemployed (6% seeking work, 16% not seeking work, 14% job seeking status unknown), 13% were students or in-training, and 17% were in vocational rehabilitation.
Our research suggests that implementing an early vocational rehabilitation programme with individuals in the hospital setting is feasible and has good potential for enhancing post-injury labour-force participation.
Wide bandgap semiconductor materials capable of detecting X-rays and gamma-rays at room temperature without cryogenic cooling have great advantages that include portability and wide-area deployment ...in nuclear and radiological threat defense. Additional major applications include medical imaging, spectroscopy, and astrophysics. Most current room-temperature ionizing radiation detector devices are fabricated from cadmium telluride (CdTe) and cadmium zinc telluride (CdZnTe). Cadmium zinc telluride selenide (CdZnTeSe or CZTS) can be grown with high crystal yield compared to CdTe and CdZnTe. Thus, CZTS has the advantage of lowering the cost of room-temperature nuclear detectors. Thick CdTe-based detectors are prone to the trapping of charge carriers, thus limiting energy resolution and efficiency. A Frisch-Grid configuration helps to solve this problem. This research is focused on optimizing the Frisch-grid configuration for a CZTS detector. The CZTS was grown by traveling heater method. Infrared images of the CZTS matrix largely showed the absence of tellurium inclusions. The resistivity of the CZTS obtained from a current-voltage plot is of the order of <inline-formula> <tex-math notation="LaTeX">10^{10}~\Omega </tex-math></inline-formula>.cm. The charge-transport characterized by measuring the electron mobility-lifetime product is <inline-formula> <tex-math notation="LaTeX">4.7 \times 10^{-3} </tex-math></inline-formula> cm 2 /V. Detector resolution was measured for various Frisch-ring widths. For a <inline-formula> <tex-math notation="LaTeX">4.8 \times 4.9 \times 9.7 </tex-math></inline-formula> mm 3 detector, the best Frisch-ring widths were found to be 3-4 mm. A detector resolution of 1.35% full-width-at-half-maximum was obtained for the 3-mm width at −2300 V bias voltage for the 662-keV gamma peak of 137 Cs. A resolution of 1.36% was obtained for the 4-mm width at −1800 V applied bias.
The aim of this study was to describe the association of the metabolic syndrome with demographic characteristics and to identify modifiable risk factors for development of the metabolic syndrome.
Men ...and women (55%) aged 18-30 years from the Coronary Artery Risk Development in Young Adults (CARDIA) study without the metabolic syndrome at baseline (n = 4,192, 49% black) were followed-up from 1985 to 2001. Incident metabolic syndrome, defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, was ascertained 7, 10, and 15 years after baseline. Risk factors were measured via clinical examination and standardized questionnaires.
The age-adjusted rate of metabolic syndrome was 10 per 1,000 person-years (n = 575). Metabolic syndrome risk increased with age and was higher among black participants and those with less than a high school education. Higher baseline BMI, no alcohol intake (versus one to three drinks per day), higher intake of dietary carbohydrates, and lower intake of crude fiber were each associated with an increased risk for the metabolic syndrome (relative risk RR ranging from 1.3 to 1.9), and physical activity was protective (RR 0.84 95% CI 0.76-0.92). In models adjusting simultaneously for all factors, black participants and women were less likely to develop metabolic syndrome. Risk for metabolic syndrome increased 23% (20-27%) per 4.5 kg (10 lb) of weight gained, whereas regular physical activity over time versus low activity was protective (RR 0.49 0.34-0.70).
BMI and weight gain are important risk factors for the metabolic syndrome. Regular physical activity may counter this risk.
Abstract Active release antimicrobial coatings for medical devices have been developed to prevent and treat biofilm implant-related infections. To date, only a handful of coatings have been put into ...clinical use, with limited success. In this study, a novel antimicrobial compound was incorporated into a silicone (polydimethylsiloxane or PDMS) polymer to develop a novel active release coating that addressed several limitations of current device coatings. The efficacy of this coating was optimized using an in vitro flow cells system, then translated to an animal model of a simulated Type IIIB open fracture wherein well-established biofilms were used as initial inocula. Results indicated that the novel coating was able to prevent infection in 100% (9/9) of animals that were treated with biofilms and the novel coating (treatment group). In contrast, 100% (9/9) of animals that were inoculated with biofilms and not treated with the coating (positive control), did develop infection. Nine animals were used as negative controls, i.e., those that were not treated with biofilms, and showed a rate of infection of 11% (1/9). Eight animals were treated with the novel coating only to determine its effect on host tissue. Results indicated that the novel active release coating may have significant promise for future application to prevent biofilm implant-related infections in patients.
The CONSORT 2010 statement provides minimum guidelines for reporting randomised trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More ...recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders), and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human–AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret, and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.
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