Artificial Intelligence and Technology Collaboratories: Innovating aging research and Alzheimer's care.

This perspective outlines the Artificial Intelligence and Technology Collaboratories (AITC) at Johns Hopkins University, University of Pennsylvania, and University of Massachusetts, highlighting their roles in developing AI-based technologies for older adult care, particularly targeting Alzheimer's disease (AD). These National Institute on Aging (NIA) centers foster collaboration among clinicians, gerontologists, ethicists, business professionals, and engineers to create AI solutions. Key activities include identifying technology needs, stakeholder engagement, training, mentoring, data integration, and navigating ethical challenges. The objective is to apply these innovations effectively in real-world scenarios, including in rural settings. In addition, the AITC focuses on developing best practices for AI application in the care of older adults, facilitating pilot studies, and addressing ethical concerns related to technology development for older adults with cognitive impairment, with the ultimate aim of improving the lives of older adults and their caregivers. HIGHLIGHTS: Addressing the complex needs of older adults with Alzheimer's disease (AD) requires a comprehensive approach, integrating medical and social support. Current gaps in training, techniques, tools, and expertise hinder uniform access across communities and health care settings. Artificial intelligence (AI) and digital technologies hold promise in transforming care for this demographic. Yet, transitioning these innovations from concept to marketable products presents significant challenges, often stalling promising advancements in the developmental phase. The Artificial Intelligence and Technology Collaboratories (AITC) program, funded by the National Institute on Aging (NIA), presents a viable model. These Collaboratories foster the development and implementation of AI methods and technologies through projects aimed at improving care for older Americans, particularly those with AD, and promote the sharing of best practices in AI and technology integration. Why Does This Matter? The National Institute on Aging (NIA) Artificial Intelligence and Technology Collaboratories (AITC) program's mission is to accelerate the adoption of artificial intelligence (AI) and new technologies for the betterment of older adults, especially those with dementia. By bridging scientific and technological expertise, fostering clinical and industry partnerships, and enhancing the sharing of best practices, this program can significantly improve the health and quality of life for older adults with Alzheimer's disease (AD).

Explainable Artificial Intelligence to Identify Dosimetric Predictors of Toxicity in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Secondary Analysis of RTOG 0617.

PURPOSE: Dosimetric predictors of toxicity in patients treated with definitive chemoradiation for locally advanced non-small cell lung cancer are often identified through trial and error. This study used machine learning (ML) and explainable artificial intelligence to empirically characterize dosimetric predictors of toxicity in patients treated as part of a prospective clinical trial. METHODS AND MATERIALS: A secondary analysis of the Radiation Therapy Oncology Group (RTOG) 0617 trial was performed. Multiple ML models were trained to predict grade ≥3 pulmonary, cardiac, and esophageal toxicities using clinical and dosimetric features. Model performance was evaluated using the area under the curve (AUC). The best performing model for each toxicity was explained using the Shapley Additive Explanation (SHAP) framework; SHAP values were used to identify relevant dosimetric thresholds and were converted to odds ratios (ORs) with confidence intervals (CIs) generated using bootstrapping to obtain quantitative measures of risk. Thresholds were validated using logistic regression. RESULTS: The best-performing models for pulmonary, cardiac, and esophageal toxicities, outperforming logistic regression, were extreme gradient boosting (AUC, 0.739), random forest (AUC, 0.706), and naive Bayes (AUC, 0.721), respectively. For pulmonary toxicity, thresholds of a mean dose >18 Gy (OR, 2.467; 95% CI, 1.049-5.800; P = .038) and lung volume receiving ≥20 Gy (V20) > 37% (OR, 2.722; 95% CI, 1.034-7.163; P = .043) were identified. For esophageal toxicity, thresholds of a mean dose >34 Gy (OR, 4.006; 95% CI, 2.183-7.354; P < .001) and V20 > 37% (OR, 3.725; 95% CI, 1.308-10.603; P = .014) were identified. No significant thresholds were identified for cardiac toxicity. CONCLUSIONS: In this data set, ML approaches validated known dosimetric thresholds and outperformed logistic regression at predicting toxicity. Furthermore, using explainable artificial intelligence, clinically useful dosimetric thresholds might be identified and subsequently externally validated.

Corrigendum: Molecular epidemiology and comparative genomics of carbapenemase-producing Escherichia coli isolates from 19 tertiary hospitals in China from 2019 to 2020.

[This corrects the article DOI: 10.3389/fmicb.2023.1056399.].

Molecular epidemiology and comparative genomics of carbapenemase-producing Escherichia coli isolates from 19 tertiary hospitals in China from 2019 to 2020.

Background: The clinical use of carbapenems is facing challenges due to increased carbapenemase-producing Escherichia coli (CP-EC) infections over the past decade. Meanwhile, whole-genome sequencing (WGS) is an important method for bacterial epidemiological research. We aim to provide more gene-based surveys to explore the genomics and occurrence of CP-EC in China. Methods: A total of 780 Escherichia coli isolates were collected by the China Antimicrobial Resistance Surveillance Trial (CARST) from 2019 to 2020. An antibacterial susceptibility test was performed by using the agar dilution method. CP-EC were detected by the modified carbapenem inactivation method (mCIM), EDTA-modified carbapenem inactivation method (eCIM), and polymerase chain reaction (PCR). Homology analysis was performed by multilocus sequence typing (MLST). A conjugation experiment was performed to verify the transferability of plasmids carrying carbapenemase genes. WGS was conducted to explore the gene-environment of the carbapenemase gene. Result: Of the 780 Escherichia coli isolates, 31 isolates were insensitive to carbapenem with a rate of 4%. Among them, 13 CP-EC isolates had transferability of the bla NDM gene. These isolates belonged to nine distinct sequence types (STs), with some correlation. We found that two (2/13, 15.4%) of the CP-EC isolates that were collected from blood specimens were highly pathogenic and also showed high transferability of the bla NDM gene. In addition, eight (8/13, 61.5%) of the CP-EC isolates were found to be multidrug-resistant. Conclusion: With the increasing use of carbapenem, CP-EC isolates accounted for nearly half of the total carbapenem-insensitive Escherichia coli isolates. Our findings highlight the urgent need to pay attention to CP-EC isolates in bloodstream infections and ESBL-producing CP-EC isolates. Based on the One Health concept, we suggest various measures, including the development of bacterial vaccines, antibiotic management, and establishment of better medical environments, to avoid the outbreak of CP-EC.

mRNA Vaccine Era-Mechanisms, Drug Platform and Clinical Prospection.

Messenger ribonucleic acid (mRNA)-based drugs, notably mRNA vaccines, have been widely proven as a promising treatment strategy in immune therapeutics. The extraordinary advantages associated with mRNA vaccines, including their high efficacy, a relatively low severity of side effects, and low attainment costs, have enabled them to become prevalent in pre-clinical and clinical trials against various infectious diseases and cancers. Recent technological advancements have alleviated some issues that hinder mRNA vaccine development, such as low efficiency that exist in both gene translation and in vivo deliveries. mRNA immunogenicity can also be greatly adjusted as a result of upgraded technologies. In this review, we have summarized details regarding the optimization of mRNA vaccines, and the underlying biological mechanisms of this form of vaccines. Applications of mRNA vaccines in some infectious diseases and cancers are introduced. It also includes our prospections for mRNA vaccine applications in diseases caused by bacterial pathogens, such as tuberculosis. At the same time, some suggestions for future mRNA vaccine development about storage methods, safety concerns, and personalized vaccine synthesis can be found in the context.

Approving cancer treatments based on endpoints other than overall survival: an analysis of historical data using the PACE Continuous Innovation Indicators™ (CII).

BACKGROUND: There is an active debate about the role that endpoints other than overall survival (OS) should play in the drug approval process. Yet the term 'surrogate endpoint' implies that OS is the only critical metric for regulatory approval of cancer treatments. We systematically analyzed the relationship between U.S. Food and Drug Administration (FDA) approval and publication of OS evidence to understand better the risks and benefits of delaying approval until OS evidence is available. SCOPE: Using the PACE Continuous Innovation Indicators (CII) platform, we analyzed the effects of cancer type, treatment goal, and year of approval on the lag time between FDA approval and publication of first significant OS finding for 53 treatments approved between 1952 and 2016 for 10 cancer types (n = 71 approved indications). FINDINGS: Greater than 59% of treatments were approved before significant OS data for the approved indication were published. Of the drugs in the sample, 31% had lags between approval and first published OS evidence of 4 years or longer. The average number of years between approval and first OS evidence varied by cancer type and did not reliably predict the eventual amount of OS evidence accumulated. CONCLUSIONS: Striking the right balance between early access and minimizing risk is a central challenge for regulators worldwide. We illustrate that endpoints other than OS have long helped to provide timely access to new medicines, including many current standards of care. We found that many critical drugs are approved many years before OS data are published, and that OS may not be the most appropriate endpoint in some treatment contexts. Our examination of approved treatments without significant OS data suggests contexts where OS may not be the most relevant endpoint and highlights the importance of using a wide variety of fit-for-purpose evidence types in the approval process.

Adiponectin and Endometrial Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study evaluates the association between serum adiponectin concentrations and the risk of endometrial cancer through a comprehensive meta-analysis of currently available clinical data. METHODS: PubMed, Embase, the Chinese Biomedical Literature Database and the Science Citation Index (ISI Web of Science) were searched for studies that examined the association between blood adiponectin concentrations and the risk of endometrial cancer. Data from studies that met the inclusion criteria were systematically reviewed, and pooled analyses were performed according to the guidelines of Meta-Analysis of Observational Studies in Epidemiology and PRIMSA. RESULTS: Eight case-control studies (including 1257 endometrial cancer patients and 2008 controls) and four nested case-control studies (including 659 endometrial cancer patients and 1398 controls) were included. We found that serum adiponectin level was inversely correlated with the risk of endometrial cancer development after pooling the case-control studies (OR = 0.50, 95% CI: 0.39-0.60; P < 0.001). However, meta-analysis of nested case-control studies thus far did not support a broad linkage between serum adiponectin level and endometrial cancer, although a correlation may exist in the subgroup of postmenopausal women (OR=0.81, 95%CI: 0.65-1.00; P=0.060), particularly in postmenopausal women without current hormone replacement therapy (OR = 0.62, 95% CI: 0.44-0.86; P = 0.004). CONCLUSIONS: Meta-analysis of currently available clinical evidence supports the association between high serum adiponectin concentration and reduced risk of endometrial cancer development, particularly in the group of postmenopausal women without current hormone replacement therapy. However, additional studies with prospective design are required to fully support this linkage.

PACE Continuous Innovation Indicators-a novel tool to measure progress in cancer treatments.

Concerns about rising health care costs and the often incremental nature of improvements in health outcomes continue to fuel intense debates about 'progress' and 'value' in cancer research. In times of tightening fiscal constraints, it is increasingly important for patients and their representatives to define what constitutes 'value' to them. It is clear that diverse stakeholders have different priorities. Harmonisation of values may be neither possible nor desirable. Stakeholders lack tools to visualise or otherwise express these differences and to track progress in cancer treatments based on variable sets of values. The Patient Access to Cancer care Excellence (PACE) Continuous Innovation Indicators are novel, scientifically rigorous progress trackers that employ a three-step process to quantify progress in cancer treatments: 1) mine the literature to determine the strength of the evidence supporting each treatment; 2) allow users to weight the analysis according to their priorities and values; and 3) calculate Evidence Scores (E-Scores), a novel measure to track progress, based on the strength of the evidence weighted by the assigned value. We herein introduce a novel, flexible value model, show how the values from the model can be used to weight the evidence from the scientific literature to obtain E-Scores, and illustrate how assigning different values to new treatments influences the E-Scores. The Indicators allow users to learn how differing values lead to differing assessments of progress in cancer research and to check whether current incentives for innovation are aligned with their value model. By comparing E-Scores generated by this tool, users are able to visualise the relative pace of innovation across areas of cancer research and how stepwise innovation can contribute to substantial progress against cancer over time. Learning from experience and mapping current unmet needs will help to support a broad audience of stakeholders in their efforts to accelerate and maximise progress against cancer.

Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature.

In its classical form, embryonal rhabdomyosarcoma (ERMS, botryoid type) is a vaginal neoplasm occurring in infants and young girls and is often not considered in the differential diagnosis of uterine corpus and cervical spindle cell tumors in adult women. Clinicopathologic and immunohistochemical features of 25 cases of ERMS in women 20 years of age or older were analyzed. Patient age ranged from 20 to 89 years (mean, 44.4 y; median, 46 y), with 8 patients aged 20 to 39 years, 14 patients aged 40 to 59 years, and 3 patients older than 60 years of age. Tumors originated in the cervix in 20 cases and in the uterine corpus in 5. They were characterized by an edematous hypocellular spindle cell proliferation, typically with cellular condensation beneath epithelial surfaces (cambium layer), in which tightly packed hypercellular foci were scattered. Neoplastic cells had hyperchromatic nuclei and minimal cytoplasm, usually with delicate cytoplasmic processes. Occasionally, elongated or globular cells with eosinophilic cytoplasm (rhabdomyoblasts) were evident, but cytoplasmic cross-striations were only rarely identified. Apoptotic bodies and mitotic figures were usually identified in the hypercellular foci. Hemorrhage was common, often making recognition of the hypercellular foci difficult. Desmin and myogenin were coexpressed in 22 of 23 (95.6%) tumors evaluated. Proliferative activity, as assessed by Ki-67 expression, was notably elevated in all tumors evaluated, typically concentrated in the hypercellular foci. Estrogen and progesterone receptors were expressed focally in only 3 of 12 (25%) and 1 of 8 (12.5%) tumors evaluated, respectively. Follow-up was available in 7 cases. Five patients were alive without evidence of disease with follow-up of 3 to 8 years, and 1 patient was alive with disease at 5 months. One patient died at 5 months with pulmonary nodules, but it was not determined whether this was due to metastatic ERMS or the patient's known ductal breast carcinoma. ERMS has a broader clinical profile than classically expected and should be considered in the differential diagnosis of a uterine corpus or cervical spindle cell tumor, regardless of patient age. Recognition can be rendered difficult by the hypocellular background, which can suggest a benign polyp or low-grade tumor, and hemorrhage, which can obscure the characteristic hypercellular foci. Identification of hypercellular foci in which mitotic activity and apoptotic bodies are found, desmin and myogenin are coexpressed, proliferative activity is notably elevated, and hormone receptor expression is usually absent is very useful for establishing the diagnosis.

Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma.

It has been reported that the diagnosis of serous tubal intraepithelial carcinoma (STIC) is not optimally reproducible on the basis of only histologic assessment. Recently, we reported that the use of a diagnostic algorithm that combines histologic features and coordinate immunohistochemical expression of p53 and Ki-67 substantially improves reproducibility of the diagnosis. The goal of the current study was to validate this algorithm by testing a group of 6 gynecologic pathologists who had not participated in the development of the algorithm (3 faculty and 3 fellows) but who were trained in its use by referring to a website designed for the purpose. They then reviewed a set of microscopic slides, which contained 41 mucosal lesions of the fallopian tube. Overall consensus (≥4 of 6 pathologists) for the 4 categories of STIC, serous tubal intraepithelial lesion (our atypical intermediate category), p53 signature, and normal/reactive was achieved in 76% of the lesions, with no consensus in 24%. Combining diagnoses into 2 categories (STIC versus non-STIC) resulted in an overall consensus of 93% and no consensus in 7%. The κ value for STIC versus non-STIC among all 6 observers was also high at 0.67 and did not significantly differ, whether for faculty (κ=0.66) or fellows (κ=0.60). These findings confirm the reproducibility of this algorithm by a group of gynecologic pathologists who were trained on a website for that purpose. Accordingly, we recommend its use in research studies. Before applying it to routine clinical practice, the algorithm should be evaluated by general surgical pathologists in a community setting.

Measuring hot flashes: summary of a National Institutes of Health workshop.

The etiology and mechanism of hot flashes remain incompletely understood. Future studies of hormonal and neurologic systems may provide promising leads to improve our understanding of the basic phenomenon and perhaps also shed light on the placebo effect. However, this is likely a complex undertaking. Critical to this effort is the ability to reliably identify when a hot flash has occurred. The leading objective measure in use today--sternal skin conductance monitoring--has some limitations in ambulatory settings. However, a more severe limitation is the inability of sternal skin conductance to provide any information on duration, intensity, and interference with activities. Ultimately, researchers desire a convenient and cost-effective sensor for monitoring hot flashes without cumbersome electrodes that might become compromised if a subject experiences extensive sweating or takes a shower and one that can capture data continuously for relatively long periods of observation. However, researchers also need well-characterized methods for collecting self-reported data. If the primary concern is helping women with hot flashes find relief, then subjective measures collected through diaries or interviews cannot be dismissed. Given the importance of this information, it would make sense to undertake methodologic research to ensure that the best possible systems are used to collect valid and reliable information. The factors that we want to measure with respect to hot flashes are likely to change over time as more is learned about the underlying phenomenon. This will probably be an evolutionary process, one involving decisions about what biological factors will be most useful for the task at hand, what technologies might be available or easily adaptable, which measures should be bundled together to maximize the precision of data collected with the available technology, and the analysis of the data to generate new hypotheses and perhaps the need for new measurement tools. Investigators face several challenges when considering the design of studies of hot flashes. Substantial placebo effects and small sample sizes have produced studies with equivocal findings. The placebo effect, while remarkable in its dimensions in some studies of hot flash interventions, is not understood. Distinguishing placebo effects from the natural dissipation of symptoms over time would be extremely helpful. Similarly, the ability to induce a placebo effect to reduce the discomfort and annoyance associated with hot flashes might be helpful. The use of neuroimaging technology offers potential for greater understanding of the placebo effect. The group concluded that better measures of hot flashes require improved knowledge in several areas: The physical processes underlying hot flashes, which will identify additional factors to measure and the factors that influence the perception and reporting of hot flashes. Improved sternal skin conductance systems, with additional tools to be developed when other factors of hot flashes are identified. The performance characteristics of questionnaires and diaries to collect self-reported data on hot flash frequency. Improved and validated instruments for collecting data on intensity and interference with daily activities. The mechanism(s) of action of placebo, which may also help distinguish natural attrition of symptoms from placebo effect. Animal models to elucidate triggers and mechanisms of hot flashes and to screen potential treatments. Investigators interested in studying hot flashes face complex issues. The incomplete understanding of the basic physiology underlying hot flashes clearly calls for further work in this area. Some mechanistic studies cannot be conducted with human subjects; thus, animal models are needed. Animal models could be particularly helpful for understanding the neurobiology of hot flashes and perhaps placebo effects. Bringing scientists together from different fields would appear to be a promising approach to moving this area forward. Scientific advances are being made increasingly at the interfaces of traditional disciplines, and approaches to science are becoming more integrative. Finding appropriate collaborators from other disciplines is not necessarily easy, and meeting a collaborator from another discipline is only the first step in building a multidisciplinary research team. Effective teams begin with compelling reasons for their existence, but further incentives must be developed to ensure full realization of their potential. The success of team science depends on individuals who are comfortable with boundary-crossing activities. Working as part of a team that is seeking solutions to complex problems requires a willingness to work in an interdisciplinary environment, to collaborate with different types of organizations, and to recognize the importance of a variety of roles in the project. It is likely that a multidisciplinary approach to hot flash research would be helpful given the number of physiologic, clinical, and behavioral factors involved. For example, psychologists and sociologists could contribute to identifying factors that may influence the placebo effect, such as pill color; developing and validating questionnaire items and diary formats; ascertaining the effect of mode of data collection on the quality of the resulting data; and determining the best ways to provide information to subjects. However, if they were part of a multidisciplinary team that included basic scientists, clinicians, and bioengineers, different questions might be asked, and better tools might be developed to collect both subjective and objective data on hot flashes. The increasing emphasis on collaborative science is also embraced at the NIH level. Since May 2002, the NIH has been engaged in a series of activities collectively known as the "NIH Roadmap," whose goal, in keeping with the NIH mission of uncovering new knowledge about the prevention, detection, diagnosis, and treatment of disease and disability, is to accelerate both the pace of discovery in these key areas and the translation of therapies from bench to bedside. The timing of this workshop to assess measures of hot flashes appears auspicious for several reasons. First, the issue of refining and validating self-reported measures of symptoms through the use of biomarkers and multidisciplinary research teams is consonant with an NIH Roadmap initiative. Second, the new National Institute for Biomedical Imaging and Bioengineering at the NIH offers impetus for linking biomedical, social, and behavioral scientists with bioengineers to assess and improve existing technology or develop new technologies to collect data on physiological markers specific to hot flashes. Third, people are already purchasing and using CAM modalities or are resuming hormone therapy for relief of hot flashes, and they and their clinicians are eager for and deserve more information on the safety and efficacy of these remedies.

Health and behavior risks of adolescents with mixed-race identity.

OBJECTIVES: This study compared the health and risk status of adolescents who identify with 1 race with those identifying with more than 1 race. METHODS: Data are derived from self-reports of race, using the National Longitudinal Study of Adolescent Health (Add Health), which provides a large representative national sample of adolescents in grades 7 through 12. Respondents could report more than 1 race. RESULTS: Mixed-race adolescents showed higher risk when compared with single-race adolescents on general health questions, school experience, smoking and drinking, and other risk variables. CONCLUSIONS: Adolescents who self-identify as more than 1 race are at higher health and behavior risks. The findings are compatible with interpreting the elevated risk of mixed race as associated with stress.