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The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer's guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.
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Pruebas de Carcinogenicidad , Animales , Pruebas de Carcinogenicidad/métodos , Pruebas de Carcinogenicidad/normas , Neoplasias/inducido químicamente , Neoplasias/patología , Estados Unidos , Ratas , United States Food and Drug Administration , Roedores , Ratones , Guías como Asunto , Interpretación Estadística de DatosRESUMEN
BACKGROUND: Assessment of individual and population-level dietary intake is critical for public health surveillance, epidemiology, and dietary intervention research. In recognition of that need, the National Insitutes of Health (NIH) has a history of funding research projects designed to support the development, implementation, and refinement of tools to assess dietary intake in humans. OBJECTIVES: This report provides data and information on NIH-funded dietary intake assessment methodological research over the period of 2012-2021. METHODS: Data were extracted from an internal NIH data system using the Research, Condition, and Disease Categorization (RCDC) spending category for Nutrition. Data were then examined to identify research focused on dietary assessment tools or methods to capture or analyze dietary intake. RESULTS: Over the decade of 2012-2021, NIH supported 46 grants and 2 large contracts specific to dietary assessment methods development. The top 6 Institutes and Offices funding dietary assessment methods research were identified. Most projects were limited to adults. Projects ranged from novel methods to capture dietary intake, and refinement of analytical methods, to biomarkers of dietary intake. One key contract supported the automated self-administered 24-h dietary assessment tool (ASA24), a widely used, free tool available to the research community for assessing dietary intake. CONCLUSIONS: NIH's support for dietary assessment methods development over this 10-y period was small but grew over time with an expanding number and variety of methods, data sources, and technological advancements in the assessment of dietary intake. NIH remains committed to supporting research seeking to advance the field of dietary assessment methods research.
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National Institutes of Health (U.S.) , Evaluación Nutricional , Adulto , Estados Unidos , Humanos , Dieta , Organización de la Financiación , Ingestión de AlimentosRESUMEN
BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. INTERPRETATION: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. FUNDING: UK Vaccine Taskforce and National Institute for Health Research.
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Vacuna BNT162/administración & dosificación , COVID-19/prevención & control , ChAdOx1 nCoV-19/administración & dosificación , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal , Adulto , Anciano , Anciano de 80 o más Años , Vacuna BNT162/inmunología , COVID-19/inmunología , ChAdOx1 nCoV-19/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Seguridad del Paciente , SARS-CoV-2 , Reino UnidoRESUMEN
This article describes the Society of Toxicologic Pathology's (STP) five recommended ("best") practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds ("no observed adverse effect level" and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination.
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Patólogos , Revisión por Pares , Animales , Humanos , Microscopía , Nivel sin Efectos Adversos ObservadosRESUMEN
The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.
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Patólogos , Pruebas de Toxicidad , Animales , Documentación , Femenino , Humanos , Masculino , Políticas , Proyectos de InvestigaciónRESUMEN
As ovarian toxicity is often a safety concern for cancer therapeutics, identification of ovarian pathology is important in early stages of preclinical drug development, particularly when the intended patient population include women of child-bearing potential. Microscopic evaluation by pathologists of hematoxylin and eosin (H&E)-stained tissues is the current gold standard for the assessment of organs in toxicity studies. However, digital pathology and advanced image analysis are being explored with greater frequency and broader applicability to tissue evaluations in toxicologic pathology. Our objective in this work was to develop an automated method that rapidly enumerates rat ovarian corpora lutea on standard H&E-stained slides with comparable accuracy to the gold standard assessment by a pathologist. Herein, we describe an algorithm generated by a deep learning network and tested on 5 rat toxicity studies, which included studies that both had and had not previously been diagnosed with effects on number of ovarian corpora lutea. Our algorithm could not only enumerate corpora lutea accurately in all studies but also revealed distinct trends for studies with and without reproductive toxicity. Our method could be a widely applied tool to aid analysis in general toxicity studies.
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Cuerpo Lúteo/efectos de los fármacos , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador/métodos , Animales , Femenino , Ratas , Ratas Sprague-Dawley , Estudios RetrospectivosRESUMEN
The Society of Toxicologic Pathology (STP) explored current institutional practices for selecting between non-blinded versus blinded histopathologic evaluation during Good Laboratory Practice (GLP)-compliant, regulatory-type animal toxicity studies using a multi-question survey and STP-wide discussion (held at the 2019 STP annual meeting). Survey responses were received from 107 individuals representing 83 institutions that collectively employ 589 toxicologic pathologists. Most responses came from industry (N = 46, mainly biopharmaceutical or contract research organizations) and consultants (N = 24). For GLP-compliant animal toxicity studies, histopathologic evaluation usually involves initial (primary) non-blinded analysis, with post hoc informal blinded re-examination at the study pathologist's discretion to confirm subtle findings or establish thresholds. Initial blinded histopathologic evaluation sometimes is chosen by study pathologists to test formal hypotheses and/or by sponsors to address non-pathologist expectations about histopathology data objectivity. Current practice is that a blinded histopathologic evaluation is documented only if formal blinding (ie, using slides with coded labels) is employed, using simple statements without detailed methodology in the study protocol (or an amendment) and/or pathology report. Blinding is not an appropriate strategy for the initial histopathologic evaluation performed during pathology peer reviews of GLP-compliant animal toxicity studies. [Box: see text].
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Pruebas de Toxicidad/métodos , Animales , Animales de Laboratorio , Humanos , Patólogos , Patología/métodos , Revisión por Pares , Proyectos de Investigación , Encuestas y Cuestionarios , Toxicología/métodosRESUMEN
D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.
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Encefalopatías Metabólicas Innatas/tratamiento farmacológico , Cardiomiopatías/tratamiento farmacológico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Mutación/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Encefalopatías Metabólicas Innatas/genética , Modelos Animales de Enfermedad , Isocitrato Deshidrogenasa/genética , Ratones , Mutación/genéticaRESUMEN
Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies.
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Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Toxicología/métodos , Toxicología/normas , Animales , Adhesión a Directriz , Humanos , Patología Clínica/métodos , Patología Clínica/normas , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/normasRESUMEN
The U.S. Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a multitiered approach to determine the potential for environmental chemicals to alter the endocrine system. The Pubertal Development and Thyroid Function in Intact Juvenile/Peripubertal Female and Male Rats (OPPTS 890.1450, 890.1500) are 2 of the 9 EDSP tier 1 test Guidelines, which assess upstream mechanistic pathways along with downstream morphological end points including histological evaluation of the kidneys, thyroid, and select male/female reproductive tissues (ovaries, uterus, testes, and epididymides). These assays are part of a battery of in vivo and in vitro screens used for initial detection of test article endocrine activity. In this Points to Consider article, we describe tissue processing, evaluation, and nomenclature to aid in standardization of assay results across laboratories. Pubertal assay end points addressed include organ weights, estrous cyclicity, clinical pathology, hormonal assays, and histological evaluation. Potential treatment-related findings that may indicate endocrine disruption are reviewed. Additional tissues that may be useful in assessment of endocrine disruption (vagina, mammary glands, and liver) are discussed. This Points to Consider article is intended to provide information for evaluating peripubertal tissues within the context of individual assay end points, the overall pubertal assay, and tier I assays of the EDSP program.
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Disruptores Endocrinos/toxicidad , Pubertad/efectos de los fármacos , Pruebas de Función de la Tiroides/métodos , Glándula Tiroides/efectos de los fármacos , Pruebas de Toxicidad/métodos , Animales , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Tamaño de los Órganos/efectos de los fármacos , RatasRESUMEN
The U.S. dietary supplement market increased by 7.5% in 2012 compared with 2011, reaching $32.5 billion in sales. Therefore, federally supported research on dietary supplements is important to determine their health effects, safety, and efficacy. A portfolio analysis was performed across the NIH and the Office of Dietary Supplements (ODS) for fiscal years (FYs) 2009-2011 by using the databases Human Nutrition Research Information Management (HNRIM) and Computer Access to Research on Dietary Supplements (CARDS). The results indicated that total NIH dietary supplement-related funding for FYs 2009-2011 was $855 million ($295 million in 2009, $311 million in 2010, and $249 million in 2011). The institutes and centers with the highest investment in dietary supplement research were as follows: the National Heart, Lung, and Blood Institute ($135 million); the National Cancer Institute ($188 million); the National Center for Complementary and Alternative Medicine ($99 million); the National Institute of Diabetes and Digestive and Kidney Diseases ($68 million); the National Institute of Environmental Health Sciences ($58 million); and the ODS ($32 million). The dietary supplement ingredients receiving the most funding were botanicals (22%), vitamins (20%), lipids (14%), and minerals and trace elements (10%). The top 3 outcome research areas were cancer (61% of total dietary supplement investment), cardiovascular disease (47%), and women's reproductive health (38%). In FYs 2009, 2010, and 2011, the ODS provided 3.5%, 3.6%, and 4.1%, respectively, of the NIH investment in dietary supplement research. ODS funding focused on cellular, enzymatic, or molecular mechanisms (64% of total ODS funding). This portfolio analysis demonstrates that the NIH has committed substantial funding to dietary supplement research in an effort to expand the scientific knowledge base on the efficacy and safety of dietary supplements.
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Investigación Biomédica , Suplementos Dietéticos , Investigación Biomédica/economía , Investigación Biomédica/tendencias , Suplementos Dietéticos/efectos adversos , Suplementos Dietéticos/economía , Humanos , National Institutes of Health (U.S.) , Apoyo a la Investigación como Asunto , Estados UnidosRESUMEN
The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.
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Dieta , Errores Innatos del Metabolismo/dietoterapia , Fenómenos Fisiológicos de la Nutrición , Suplementos Dietéticos , Manejo de la Enfermedad , Vías de Administración de Medicamentos , Humanos , Errores Innatos del Metabolismo/genética , Enfermedades Raras , Estados UnidosRESUMEN
BACKGROUND: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms. METHODS: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation. RESULTS: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms. CONCLUSIONS: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.
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COVID-19 , Vacunas Virales , Femenino , Humanos , Anciano , Masculino , Vacunas contra la COVID-19 , Vacuna BNT162 , ChAdOx1 nCoV-19 , COVID-19/prevención & control , SARS-CoV-2 , Inmunidad , Reino Unido , Inmunoglobulina G , Anticuerpos Antivirales , Vacunación , Inmunogenicidad VacunalRESUMEN
The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the male reproductive system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the Internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the male reproductive system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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Investigación Biomédica/normas , Enfermedades de los Genitales Masculinos/patología , Genitales Masculinos/patología , Terminología como Asunto , Animales , Animales de Laboratorio , Enfermedades de los Genitales Masculinos/clasificación , Genitales Masculinos/química , Genitales Masculinos/citología , Histocitoquímica , Masculino , Ratones , RatasRESUMEN
BACKGROUND: Evidence for diet and nutrition's role in the cancer continuum is inconsistent and requires further study. Although more investigation is needed, the National Cancer Institute (NCI) funding for nutrition has decreased. METHODS: To examine nutrition research funding at the NCI, a portfolio analysis was undertaken for fiscal year (FY) 2018. Nutrition and other cancer-related terms were searched using the National Institutes of Health Query View and Report grants management dashboard. Grants were categorized by mechanism, funding status, applicant characteristics, funding opportunity announcement type, award type, and study characteristics. RESULTS: A total of 18â233 NCI grant applications were submitted in FY 2018; 12% were funded. Of the 653 nutrition-related grant applications received, 69 (11%) were funded. Funding status of nutrition grants did not differ statistically based on the type of funding opportunity announcement and were higher for applications classified as investigator initiated. Early stage investigators' nutrition applications were funded less than other investigators. Only 4% and 6% of overall and funded nutrition grant applications were submitted by registered dietitian nutritionist primary investigators, respectively. Average FY 2018 award amounts for funded nutrition and overall grant applications were approximately US $399 000 and approximately US $703 000, respectively. Although the percentage of NCI nutrition grants funded was similar to other grant funding at NCI in FY 2018, between FY 2012 and FY 2018, NCI decreased overall nutrition funding by 44%. CONCLUSIONS: Average grant award amounts for nutrition were less compared with overall NCI-funded grant applications and other topics. Our analysis highlights potential opportunities for greater investment in nutrition research at the NCI.
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Distinciones y Premios , Neoplasias , Organización de la Financiación , Humanos , National Cancer Institute (U.S.) , National Institutes of Health (U.S.) , Neoplasias/terapia , Investigadores , Estados UnidosRESUMEN
INTRODUCTION: Nutrition health disparities include differences in incidence, prevalence, morbidity, and mortality of diet-related diseases and conditions. Often, race, ethnicity, and the social determinants of health are associated with dietary intake and related health disparities. This report describes the nutrition health disparities research supported by NIH over the past decade and offers future research opportunities relevant to NIH's mission as described in the Strategic Plan for NIH Nutrition Research. METHODS: Data were extracted from an internal reporting system from FY2010 to FY2019 using the Research, Condition, and Disease Categorization spending categories for Nutrition and Health Disparities. RESULTS: Over the past decade, NIH-supported nutrition and health disparities research increased, from 860 grants in 2010 to 937 grants in FY2019, whereas total nutrition and health disparities funding remained relatively stable. The top 5 Institutes/Centers that funded nutrition and health disparities research (on the basis of both grant numbers and dollars) were identified. Principal areas of focus included several chronic diseases (e.g., obesity, diabetes, cancer, heart disease) and research disciplines (e.g., clinical research and behavioral and social science). Focus areas related to special populations included pediatrics, minority health, aging, and women's health. CONCLUSIONS: The gaps and trends identified in this analysis highlight the need for future nutrition and health disparities research, including a focus on American Indian and Asian populations and the growing topics of rural health, maternal health, and food insecurity. In alignment with the Strategic Plan for NIH Nutrition Research, health equity may be advanced through innovative research approaches to develop effective targeted interventions to address these disparities.
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Investigación Biomédica , Organización de la Financiación , Niño , Dieta , Etnicidad , Femenino , Humanos , National Institutes of Health (U.S.) , Estado Nutricional , Estados Unidos , Salud de la MujerRESUMEN
OBJECTIVES: To evaluate the persistence of immunogenicity three months after third dose boosters. METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study. RESULTS: Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 µg) or BNT (30 µg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 µg) versus BNT (30 µg) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses. CONCLUSIONS: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses.
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COVID-19 , Vacunas Virales , Ad26COVS1 , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , ChAdOx1 nCoV-19 , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Persona de Mediana Edad , SARS-CoV-2 , Reino Unido , Vacunas de ARNmRESUMEN
BACKGROUND: Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19. METHODS: The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing. FINDINGS: Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6-77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3-214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030-27 162), which increased to 37 460 ELU/mL (31 996-43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41-1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996-30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826-64 452), with a geometric mean fold change of 2·19 (1·90-2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37-14·32) and 15·90 (12·92-19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24-16·54] in the BNT162b2 group and 6·22 [3·90-9·92] in the mRNA-1273 group). INTERPRETATION: Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose. FUNDING: UK Vaccine Task Force and National Institute for Health Research.
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Vacunas contra la COVID-19 , COVID-19 , Vacuna nCoV-2019 mRNA-1273 , Anciano , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , ChAdOx1 nCoV-19 , Femenino , Humanos , Inmunogenicidad Vacunal , Inmunoglobulina G , Masculino , Persona de Mediana Edad , SARS-CoV-2RESUMEN
Over one-half of U.S. adults use dietary supplements, so federally supported research into the safety and effectiveness of these compounds is important for the health of many Americans. Data collected in the Computer Access to Research on Dietary Supplements database, which compiles federally sponsored dietary supplement-related research, are useful to scientists in determining the type of dietary supplement research that federal agencies are currently funding and where research gaps exist. This article describes the dietary supplement-related research funded by the NIH and the USDA. Between fiscal years 1999 and 2007, the number of research projects and funding for dietary supplement research more than doubled. During that period, NIH funded 6748 dietary supplement-related projects at a cost of $1.9 billion and the USDA funded 2258 projects at a cost of $347 million. The top funded dietary supplement ingredient categories were vitamins and minerals, botanicals, phytochemicals, and fatty acids. Cancer was by far the most frequent health outcome in dietary supplement research funding, nearly double the next closest health outcome category. Other health outcomes with the greatest funding were cellular and molecular mechanisms, cardiovascular health, women's reproductive health, and immune function. The greatest number of dietary supplement research projects are funded by the NIH National Cancer Institute, the NIH National Center for Complementary and Alternative Medicine, the NIH Office of Dietary Supplements, and the USDA Agricultural Research Service.