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The National Institutes of Health-US Food and Drug Administration Joint Leadership Council Next-Generation Sequencing and Radiomics Working Group was formed by the National Institutes of Health-Food and Drug Administration Joint Leadership Council to promote the development and validation of innovative next-generation sequencing tests, radiomic tools, and associated data analysis and interpretation enhanced by artificial intelligence and machine learning technologies. A 2-day workshop was held on September 29-30, 2021, to convene members of the scientific community to discuss how to overcome the "ground truth" gap that has frequently been acknowledged as 1 of the limiting factors impeding high-quality research, development, validation, and regulatory science in these fields. This report provides a summary of the resource gaps identified by the working group and attendees, highlights existing resources and the ways they can potentially be employed to accelerate growth in these fields, and presents opportunities to support next-generation sequencing and radiomic tool development and validation using technologies such as artificial intelligence and machine learning., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Proteomics has emerged as a powerful tool for studying cancer biology, developing diagnostics, and therapies. With the continuous improvement and widespread availability of high-throughput proteomic technologies, the generation of large-scale proteomic data has become more common in cancer research, and there is a growing need for resources that support the sharing and integration of multi-omics datasets. Such datasets require extensive metadata including clinical, biospecimen, and experimental and workflow annotations that are crucial for data interpretation and reanalysis. The need to integrate, analyze, and share these data has led to the development of NCI's Proteomic Data Commons (PDC), accessible at https://pdc.cancer.gov. As a specialized repository within the NCI Cancer Research Data Commons (CRDC), PDC enables researchers to locate and analyze proteomic data from various cancer types and connect with genomic and imaging data available for the same samples in other CRDC nodes. Presently, PDC houses annotated data from more than 160 datasets across 19 cancer types, generated by several large-scale cancer research programs with cohort sizes exceeding 100 samples (tumor and associated normal when available). In this article, we review the current state of PDC in cancer research, discuss the opportunities and challenges associated with data sharing in proteomics, and propose future directions for the resource., Significance: The Proteomic Data Commons (PDC) plays a crucial role in advancing cancer research by providing a centralized repository of high-quality cancer proteomic data, enriched with extensive clinical annotations. By integrating and cross-referencing with complementary genomic and imaging data, the PDC facilitates multi-omics analyses, driving comprehensive insights, and accelerating discoveries across various cancer types., (©2024 The Authors; Published by the American Association for Cancer Research.)

Since 2014, the NCI has launched a series of data commons as part of the Cancer Research Data Commons (CRDC) ecosystem housing genomic, proteomic, imaging, and clinical data to support cancer research and promote data sharing of NCI-funded studies. This review describes each data commons (Genomic Data Commons, Proteomic Data Commons, Integrated Canine Data Commons, Cancer Data Service, Imaging Data Commons, and Clinical and Translational Data Commons), including their unique and shared features, accomplishments, and challenges. Also discussed is how the CRDC data commons implement Findable, Accessible, Interoperable, Reusable (FAIR) principles and promote data sharing in support of the new NIH Data Management and Sharing Policy. See related articles by Brady et al., p. 1384, Pot et al., p. 1396, and Kim et al., p. 1404., (©2024 The Authors; Published by the American Association for Cancer Research.)

The spread of beta-lactamase-producing bacteria is a global public-health concern. This study aimed to explore the distribution of beta-lactamases reported in three sampling sources (cecal, retail meat, and human) collected as part of integrated surveillance in the United States. We retrieved and analyzed data from the United States National Antimicrobial Resistance Monitoring Systems (NARMS) from 2002 to 2021. A total of 115 beta-lactamase genes were detected in E. coli, Salmonella enterica, Campylobacter, Shigella and Vibrio: including 35 genes from cecal isolates, 32 genes from the retail meat isolates, and 104 genes from the human isolates. Three genes in E. coli (bla CMY-2, bla TEM-1A , and bla TEM-1B ), 6 genes in Salmonella enterica (bla CARB-2 , bla CMY-2 , bla CTXM-65 , bla TEM-1A , bla TEM-1B , and bla HERA-3 ), and 2 genes in Campylobacter spp. (bla OXA-61 and bla OXA-449 ) have been detected across food animals (cattle, chicken, swine, and turkey) and humans over the study period. bla CTXM-55 has been detected in E. coli isolates from the four food animal sources while bla CTXM-15 and bla CTXM-27 were found only in cattle and swine. In Salmonella enterica, bla CTXM-2 , bla CTXM-9 , bla CTXM-14 , bla CTXM-15 , bla CTXM-27 , bla CTXM-55 , and bla NDM-1 were only detected among human isolates. bla OXAs and bla CARB were bacteria-specific and the only beta-lactamase genes detected in Campylobacter spp. and Vibrio spp respectively. The proportions of beta-lactamase genes detected varies from bacteria to bacteria. This study provided insights on the beta-lactamase genes detected in bacteria in food animals and humans in the United States. This is necessary for better understanding the molecular epidemiology of clinically important beta-lactamases in one health interface., Competing Interests: Declaration of Competing Interest We hereby declare no financial/personal interest or belief that could affect the objectivity of this research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The lack of harmonization in the post-approval changes (PACs) classifications for pharmaceutical products may have an impact on the efficient implementation of PACs and in the supply of medicine, jeopardizing the continuity of therapies, especially in the case of chronic diseases. The percentage of similarity between the PACs classifications existing between countries of Latin America (Mexico, Brazil, Colombia, Venezuela, Argentina, Chile, Ecuador, Peru, and Central America) versus Europe and the United States (US) has been calculated, focused on the PACs for chemical products and on the minor and moderate variations as defined in the European Union (EU) 1 , 2 and US 3 these countries could further align their PACs classification with the EU and US regulations. This could also be an opportunity for other countries of the Latin America region to recognize and adopt PACs classifications aligned to the EU or United States, which would also support the inclusion of reliance processes in their regulation for already considered/recognized reference countries. This would guarantee more health authority efficiency and optimization as well as more uniform implementation of PACs globally.4 and the Pharmaceutical Inspection Co-operation Scheme, 5 these countries could further align their PACs classification with the EU and US regulations. This could also be an opportunity for other countries of the Latin America region to recognize and adopt PACs classifications aligned to the EU or United States, which would also support the inclusion of reliance processes in their regulation for already considered/recognized reference countries. This would guarantee more health authority efficiency and optimization as well as more uniform implementation of PACs globally., Competing Interests: Declaration of Competing Interest All the authors are Sanofi employees and may hold shares and/or stock options in the company. All the authors hold positions within the pharmaceutical industry, but they have not received any grant, honoraria, or other compensation to author the manuscript. The views expressed in this research paper are the independent views of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of their respective companies or any other affiliation. The authors have indicated that they have no other conflicts of interest about the content of this article. All the authors were involves in the study design, the collection, analysis and interpretation of data, and the writing of the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite progress in genomic and proteomic technology and applications, the validation of cancer biomarkers of use as clinical early detection diagnostics has remained elusive. As described in this brief viewpoint, there are now recognized to be many types of clinical biomarkers and proteomic analyses, particularly when combined with other 'omic analyses, have been effective in many such biomarker identifications. However, in the area of early diagnosis of cancers, the problems associated with the conversion from identification to diagnostic have largely not been overcome. Notably, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI), has been particularly successful in refining the analytical steps needed to tackle this challenging issue and has provided positive insight into how to solve many of the underlying problems. The potential for developing clinical diagnostics for early detection of highly lethal cancers and possible new therapeutic strategies through proteomic analyses, as seen through these CPTAC successes, is more promising than ever., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The Veterans Health Administration (VA) primary care is organized as a Patient Centered Medical Home (PCMH) that is based on continuity management of patient panels by interdisciplinary "teamlets" consisting of primary care providers, nurses, and clerical associates. While the teamlets are envisioned as interdisciplinary in this model, teamlet members may continue to report separately to middle management supervisors within their respective disciplines. Little is known about the role of middle managers in medical home implementation; therefore, the study purpose is to examine and characterize teamlet members' perceptions of middle managers' role in primary care operations and teamlet functioning in an outpatient setting., Methods: This study applied a formal qualitative data collection method and analysis based on semi-structured interviews of 79 frontline interdisciplinary staff (primary care providers, nurses, and clerical associates) in VA Patient Aligned Care Teams (PACT) teamlets. Interviews were analyzed using a method of constant comparison., Results: Teamlet members recognize that their supervising middle managers are essential to daily functioning of PACT teamlets in terms of clarifying roles and responsibilities, setting expectations, providing coverage strategies, supporting conflict resolution, and facilitating teamlet-initiated innovation. Teamlet members identified challenges when middle manager involvement was lacking., Conclusion: Within a multilevel system, frontline interdisciplinary staff continue to perceive the need for leadership by middle managers from their own professional disciplines for solving interdisciplinary problems, setting role-specific schedules and expectations, and fostering innovation. As such, greater focus on the structure and training of middle managers for participation in PCMH models is needed., (Published by Elsevier Inc.)

The integration of proteomics into precision oncology presents opportunities that may transform the molecular analysis of cancer and accelerate basic and clinical cancer research. This Commentary discusses the importance of international collaboration and data sharing inspired by the Cancer Moonshot to accelerate the progress of multi-omic precision medicine-an approach that addresses the global diversity of people and of cancers., (Published by Elsevier Inc.)

The National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium is applying the latest generation of proteomic technologies to genomically annotated tumors from The Cancer Genome Atlas (TCGA) program, a joint initiative of the NCI and the National Human Genome Research Institute. By providing a fully integrated accounting of DNA, RNA, and protein abnormalities in individual tumors, these datasets will illuminate the complex relationship between genomic abnormalities and cancer phenotypes, thus producing biologic insights as well as a wave of novel candidate biomarkers and therapeutic targets amenable to verification using targeted mass spectrometry methods., (©2013 AACR.)

Objective: To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice., Participants: Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report., Evidence: The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions., Consensus Process: Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012., Conclusions: The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

Background: Despite advances in antimicrobial and surgical therapy, septic arthritis remains a rheumatologic emergency that can lead to rapid joint destruction and irreversible loss of function. In adults, Staphylococcus aureus is the most common microorganism isolated from native joints. Streptococcus gordonii is a prominent member of the viridans group of oral bacteria and is among the bacteria most frequently identified as being primary agent of subacute bacterial endocarditis. To the best of our knowledge, Streptococcus gordonii has not yet been described as agent of septic arthritis., Case Presentation: We describe here two cases of septic arthritis due to Streptococcus gordonii. It gives us an opportunity to review epidemiology, diagnosis criteria and management of septic arthritis., Conclusion: Although implication of S. gordonii as aetiologic agent of subacute endocarditis is well known, this organism is a rare cause of septic arthritis. In this case, the exclusion of associated endocarditis is warranted.

Background: Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes., Methods: Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399., Findings: 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups., Interpretation: Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge., Funding: US National Institutes of Health., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Better biomarkers are urgently needed to cancer detection, diagnosis, and prognosis. While the genomics community is making significant advances in understanding the molecular basis of disease, proteomics will delineate the functional units of a cell, proteins and their intricate interaction network and signaling pathways for the underlying disease. Great progress has been made to characterize thousands of proteins qualitatively and quantitatively in complex biological systems by utilizing multi-dimensional sample fractionation strategies, mass spectrometry and protein microarrays. Comparative/quantitative analysis of high-quality clinical biospecimen (e.g., tissue and biofluids) of human cancer proteome landscape has the potential to reveal protein/peptide biomarkers responsible for this disease by means of their altered levels of expression, post-translational modifications as well as different forms of protein variants. Despite technological advances in proteomics, major hurdles still exist in every step of the biomarker development pipeline. The National Cancer Institute's Clinical Proteomic Technologies for Cancer initiative (NCI-CPTC) has taken a critical step to close the gap between biomarker discovery and qualification by introducing a pre-clinical "verification" stage in the pipeline, partnering with clinical laboratory organizations to develop and implement common standards, and developing regulatory science documents with the US Food and Drug Administration to educate the proteomics community on analytical evaluation requirements for multiplex assays in order to ensure the safety and effectiveness of these tests for their intended use.

Proteomics technologies have revolutionized cell biology and biochemistry by providing powerful new tools to characterize complex proteomes, multiprotein complexes and post-translational modifications. Although proteomics technologies could address important problems in clinical and translational cancer research, attempts to use proteomics approaches to discover cancer biomarkers in biofluids and tissues have been largely unsuccessful and have given rise to considerable skepticism. The National Cancer Institute has taken a leading role in facilitating the translation of proteomics from research to clinical application, through its Clinical Proteomic Technologies for Cancer. This article highlights the building of a more reliable and efficient protein biomarker development pipeline that incorporates three steps: discovery, verification and qualification. In addition, we discuss the merits of multiple reaction monitoring mass spectrometry, a multiplex targeted proteomics platform, which has emerged as a potentially promising, high-throughput protein biomarker measurements technology for preclinical 'verification'.

Proteomics holds great promise in personalized medicine for cancer in the post-genomic era. In the past decade, clinical proteomics has significantly evolved in terms of technology development, optimization and standardization, as well as in advanced bioinformatics data integration and analysis. Great strides have been made for characterizing a large number of proteins qualitatively and quantitatively in a proteome, including the use of sample fractionation, protein microarrays and MS. It is believed that differential proteomic analysis of high-quality clinical biospecimen (tissue and biofluids) can potentially reveal protein/peptide biomarkers responsible for cancer by means of their altered levels of expression and/or PTMs. Multiple reaction monitoring, a multiplexed platform using stable isotope dilution-MS with sensitivity and reproducibility approaching that of traditional ELISAs commonly used in the clinical setting, has emerged as a potentially promising technique for next-generation high-throughput protein biomarker measurements for diagnostics and therapeutics., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To describe the relationship between acculturation and human papillomavirus (HPV) infection among diverse US Latinas, a group at high risk for cervical cancer., Methods: Using survey and medical testing data from the 2003-2004 National Health and Nutrition Examination Survey (NHANES), we examined the relationship between acculturation level and HPV infection among diverse Latinas (n=503) and Mexican American women (n=442). Multivariable logistic regression was performed using infection with any type of HPV and with high-risk oncogenic genotypes as outcome variables., Results: More acculturated Mexican American women were more likely to be infected with high-risk HPV than less acculturated women. In multivariate analyses, Mexican Americans with higher levels of self-rated English language ability (2.48 OR, 95% CI: 1.42-4.33); with birth in the US (2.07 OR, 95% CI: 1.03-4.16); and with US born parents (2.98 OR, 95% CI: 1.45-3.72) were more likely to be infected with high-risk HPV genotypes. Mexican American women with higher levels of acculturation were more likely to test positive for other sexually transmitted infections., Conclusion: Higher acculturation levels related to more frequent infection with high-risk HPV genotypes and other STIs among US Mexican American women. This association may in part be due to engagement in sexual behaviors., (Copyright 2010 Elsevier Inc. All rights reserved.)

Clinical proteomics has the potential to enable the early detection of cancer through the development of multiplex assays that can inform clinical decisions. However, there has been some uncertainty among translational researchers and developers as to the specific analytical measurement criteria needed to validate protein-based multiplex assays. To begin to address the causes of this uncertainty, a day-long workshop titled "Interagency Oncology Task Force Molecular Diagnostics Workshop" was held in which members of the proteomics and regulatory communities discussed many of the analytical evaluation issues that the field should address in development of protein-based multiplex assays for clinical use. This meeting report explores the issues raised at the workshop and details the recommendations that came out of the day's discussions, such as a workshop summary discussing the analytical evaluation issues that specific proteomic technologies should address when seeking US Food and Drug Administration approval.

As a part of ongoing efforts of the NCI-FDA Interagency Oncology Task Force subcommittee on molecular diagnostics, members of the Clinical Proteomic Technology Assessment for Cancer program of the National Cancer Institute have submitted 2 protein-based multiplex assay descriptions to the Office of In Vitro Diagnostic Device Evaluation and Safety, US Food and Drug Administration. The objective was to evaluate the analytical measurement criteria and studies needed to validate protein-based multiplex assays. Each submission described a different protein-based platform: a multiplex immunoaffinity mass spectrometry platform for protein quantification, and an immunological array platform quantifying glycoprotein isoforms. Submissions provided a mutually beneficial way for members of the proteomics and regulatory communities to identify the analytical issues that the field should address when developing protein-based multiplex clinical assays.

The new allocation policy of the United Network of Organ Sharing (UNOS) based on the model for end-stage liver disease (MELD) gives candidates with stage T1 or stage T2 hepatocellular carcinoma (HCC) a priority MELD score beyond their degree of hepatic decompensation. The aim of this study was to determine the impact of the new allocation policy on HCC candidates before and after the institution of MELD. The UNOS database was reviewed for all HCC candidates listed between July 1999 and July 2002. The candidates were grouped by two time periods, based on the date of implementation of new allocation policy of February 27, 2002. Pre-MELD candidates were listed for deceased donor liver transplantation (DDLT) before February 27,2002, and post-MELD candidates were listed after February 27, 2002. Candidates were compared by incidence of DDLT, time to DDLT, and dropout rate from the waiting list because of clinical deterioration or death, and survival while waiting and after DDLT. Incidence rates calculated for pre-MELD and post-MELD periods were expressed in person years. During the study, 2,074 HCC candidates were listed for DDLT in the UNOS database. The DDLT incidence rate was 0.439 transplant/person years pre-MELD and 1.454 transplant/person years post-MELD (P < 0.001). The time to DDLT was 2.28 years pre-MELD and 0.69 years post-MELD (P < 0.001). The 5-month dropout rate was 16.5% pre-MELD and 8.5% post-MELD (P < 0.001). The 5-month waiting-list survival was 90.3% pre-MELD and 95.7% post-MELD (P < 0.001). The 5-month survival after DDLT was similar for both time periods. The new allocation policy has led to an increased incidence rate of DDLT in HCC candidates. Furthermore, the 5-month dropout rate has decreased significantly. In addition, 5-month survival while waiting has increased in the post-MELD period. Thus, the new MELD-based allocation policy has benefited HCC candidates.

Public debate about health care reform often focuses on the need for health insurance coverage, but in Latino communities many other barriers also inhibit access to medical care. In addition, basic public health services often go underfunded or ignored. Thus, health care reform efforts, nationally and in each State, must embrace a broader view of the issues if the needs of Latino communities are to be served. This report reviews and summarizes information about the mounting problems Latino communities face in gaining access to medical care. Access to appropriate medical care is reduced by numerous financial, structural, and institutional barriers. Financial barriers include the lack of health insurance coverage and low family incomes common in Latino communities. More than 7 million Latinos (39 percent) go without health insurance coverage. Latinos without health insurance receive about half as much medical care as those who are insured. Structurally, the delivery system organization rarely reflects the cultural or social concerns of the communities where they are located. Therefore, providers and patients fail to communicate their concerns adequately. These communication problems are exacerbated by the extreme shortage of Latino health care professionals and other resources available. Institutional barriers often reflect the failure to consider what it means to provide good service as well as high-quality medical care. Reducing these barriers to medical care requires modifying governmental and institutional policies, expanding the supply of competent providers, restructuring delivery system incentives to ensure primary care and public health services, and enhancing service and satisfaction with care.