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PubMed2026

HPRC2: A human pangenome reference with near-complete coverage of common genetic variation.

A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortium's (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.

Journal Article↗
PubMed2004

Effects of food attributes and feeding environment on acceptance, consumption and body weight: lessons learned in a twenty-year program of military ration research US Army Research (Part 2).

Twenty years of testing in the field has consistently revealed that food intake is inadequate when packaged military rations are fed as the sole source of food. Food intake is much lower and there is a loss of body weight. Conversely when these rations are fed to students or military personnel for periods ranging from 3 to 42 days in a cafeteria-like setting, food intake is comparable to levels of a control group provided with freshly prepared food. Under these conditions, body weight is maintained. In this review, the consumption pattern is considered in terms of characteristics of the food (acceptability, variety, portion size, beverages, serving temperature, appropriateness for time of day, monotony, and novelty) and the eating milieu (social interactions, time, ease of preparing and consuming a meal). The twenty-year program of military ration research has led us to conclude that both the food and the context must be considered in understanding and controlling food intake.

Eating↗
PubMed1994

Correlates of mortality in Russian and US women. The Lipid Research Clinics Program.

Associations between selected risk factors and 7-year all-cause mortality were studied in 2,187 Russian women and 2,146 US women who were screened as part of a US-Russian collaborative program. The US women were screened during the period 1972-1976, while the Russian women were screened from 1978 to 1982. Cigarette smoking and elevated systolic blood pressure were associated with increased mortality in both samples. High density lipoprotein (HDL) cholesterol was inversely related to mortality in US women, but there was no association of HDL cholesterol with mortality in Russian women. Prevalent angina and electrocardiographic abnormalities were associated with mortality in both samples, but the relations achieved statistical significance only in the Russian sample. The problems of cigarette smoking and elevated blood pressure should be addressed with public health measures in both countries. The absence of an association between HDL cholesterol and mortality in the Russian sample should be investigated further.

Adult↗
PubMedDate not supplied

Long-term HIV/AIDS survival estimation in the highly active antiretroviral therapy era.

BACKGROUND: Highly active antiretroviral therapy (HAART) prolongs short-term survival in patients with HIV/AIDS. HAART has only been available since 1996; thus, no long-term survival data are available. Computer simulation models extrapolating short-term survival data can provide estimates of long-term survival. These survival estimates may assist patients and clinicians in HAART treatment planning. The authors construct a computer simulation model based on observational data to estimate long-term survival in a cohort of HIV/AIDS patients undergoing treatment with HAART. METHODS: The authors use data from the Collaboration in HIV Outcomes Research-US (CHORUS) observational cohort (N = 4791), the published literature, and US Life Tables to specify a computer simulation model of expected survival accounting for baseline CD4 cell count, progressive HAART treatment failure, progressive risk of HAART on treatment mortality, and age-associated mortality. Time to treatment failure for each of three rounds of HAART and risk of mortality on-treatment were estimated using parametric survival models with censoring of follow-up fit to CHORUS data. Off-treatment survival after HAART failure was estimated from the pre-HAART literature. Age-associated mortality was taken from US Life Tables. RESULTS: Median projected survivals stratified by baseline CD4 cell count subgroups were CD4 > 200 cells/mm3, 15.4 years; CD4 < or = 200 cells/mm3, 8.5 years; and CD4 < or = 50 cells/mm3, 5.5 years. These values are 4 to 6 years longer than pre-HAART cohorts. The sensitivity analyses showed that the model survival predictions were most sensitive to the treatment failure rate, the on-treatment mortality rate, and the number of treatment rounds. CONCLUSIONS: Computer simulation modeling of long-term survival of patients with HIV/AIDS on HAART--accounting for differential treatment failure and death rates stratified by CD4 cell count and age-associated mortality--suggests a relatively consistent 4- to 6-year survival benefit over pre-HAART therapies.

Adult↗
PubMed2025

Predicting Weight Loss After Vertical Sleeve Gastrectomy Using a Whole-genome Sequencing-derived Polygenic Risk Score in the All of Us Cohort.

OBJECTIVE: To create a genome-wide polygenic risk score (PRS) to improve prediction of a 12-month percentage weight loss (WL) after vertical sleeve gastrectomy (VSG). BACKGROUND: Variability in post-VSG WL is not well explained by clinical factors. The All of Us program provides access to a 414,830 short-read whole-genome sequencing resource, enabling unbiased discovery of genetic predictors after VSG. METHODS: VSG counts, demographic, anthropomorphic and vital sign information were obtained from the linked electronic health record. The discovery cohort (DC) included participants from version 7 carried into version 8 while the validation cohort (VC) included those newly added to v8. We defined good responders and nonresponders as having WL&#xb1;1SD from the mean. Following quality filtering, we applied a 2-stage penalized-regression, followed by elastic-net logistic regression, to identify 1583 stable variants and derive &#x3b2;-weights. We then tested this PRS on the DC into a prediction model. RESULTS: We identified 395 participants in the DC and 336 participants in the VC, respectively. Of these, VSG, 44 were classified as good responders (&#x2265;37% WL) and 55 as nonresponders (&#x2264;19% WL). In the VC, 55 were classified as good responders and 48 as nonresponders. Adding the PRS to models to clinical predictors increased the area under the curve following logistic regression by 0.03; P <4.3 &#xd7; 10 -14 , random forest by 0.03; P <9.1 &#xd7; 10 -7 , decision tree by 0.05; P = 1.2 &#xd7; 10 -3 , and gradient boosting by 0.08; P <8.3 &#xd7; 10 -10 . CONCLUSIONS: Use of short-read whole-genome sequencing from All of Us (AoU) can be effectively used to generate PRS to enhance predictive WL accuracy. This work has implications for outcomes of both bariatric surgery and other surgical procedures.

Humans↗
PubMed2025

Germline Variants Influence Chronic Liver Disease Progression through Distinct Pathways.

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2&#xd7;10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7&#xd7;10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-&#x3b1; therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Journal Article↗
PubMed2004

Long-term health effects of repeated exposure to multiple vaccines.

The health of 155 former workers in a US military research program who had received multiple vaccines and 265 matched community controls was assessed. The study population was mostly male (83%) and elderly (median age, 69 years). Multiply immunized (MIP) subjects received vaccines and/or skin tests (median = 154) over a median of 17.3 years; interval from start of immunizations to survey completion was 15-55 years (mean = 43.1 years). MIP subjects characterized themselves as slightly less healthy than controls (P = 0.057). Fatigue (but no other symptom) was reported more frequently in the MIP group (P = 0.011), but was not associated with number of injections, number of vaccines, or time in program. No differences between MIP and control groups were seen for numerous self-reported medical conditions. Several statistically significant abnormalities were seen in clinical laboratory tests among MIP subjects, but none appeared to be clinically significant. A significant difference in frequency of monoclonal spikes and/or paraprotein peaks between MIP (12.5%) and control (4.5%) groups (RR = 2.7, P < 0.003) was observed; no associations with lifestyle, vaccine exposure, or medical conditions were found.

Aged↗
PubMed2022

Concordance of SARS-CoV-2 Antibody Results during a Period of Low Prevalence.

Accurate, highly specific immunoassays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to evaluate seroprevalence. This study investigated the concordance of results across four immunoassays targeting different antigens for sera collected at the beginning of the SARS-CoV-2 pandemic in the United States. Specimens from All of Us participants contributed between January and March 2020 were tested using the Abbott Architect SARS-CoV-2 IgG (immunoglobulin G) assay (Abbott) and the EuroImmun SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) (EI). Participants with discordant results, participants with concordant positive results, and a subset of concordant negative results by Abbott and EI were also tested using the Roche Elecsys anti-SARS-CoV-2 (IgG) test (Roche) and the Ortho-Clinical Diagnostics Vitros anti-SARS-CoV-2 IgG test (Ortho). The agreement and 95% confidence intervals were estimated for paired assay combinations. SARS-CoV-2 antibody concentrations were quantified for specimens with at least two positive results across four immunoassays. Among the 24,079 participants, the percent agreement for the Abbott and EI assays was 98.8% (95% confidence interval, 98.7%, 99%). Of the 490 participants who were also tested by Ortho and Roche, the probability-weighted percentage of agreement (95% confidence interval) between Ortho and Roche was 98.4% (97.9%, 98.9%), that between EI and Ortho was 98.5% (92.9%, 99.9%), that between Abbott and Roche was 98.9% (90.3%, 100.0%), that between EI and Roche was 98.9% (98.6%, 100.0%), and that between Abbott and Ortho was 98.4% (91.2%, 100.0%). Among the 32 participants who were positive by at least 2 immunoassays, 21 had quantifiable anti-SARS-CoV-2 antibody concentrations by research assays. The results across immunoassays revealed concordance during a period of low prevalence. However, the frequency of false positivity during a period of low prevalence supports the use of two sequentially performed tests for unvaccinated individuals who are seropositive by the first test. IMPORTANCE What is the agreement of commercial SARS-CoV-2 immunoglobulin G (IgG) assays during a time of low coronavirus disease 2019 (COVID-19) prevalence and no vaccine availability? Serological tests produced concordant results in a time of low SARS-CoV-2 prevalence and no vaccine availability, driven largely by the proportion of samples that were negative by two immunoassays. The CDC recommends two sequential tests for positivity for future pandemic preparedness. In a subset analysis, quantified antinucleocapsid and antispike SARS-CoV-2 IgG antibodies do not suggest the need to specify the antigen targets of the sequential assays in the CDC's recommendation because false positivity varied as much between assays targeting the same antigen as it did between assays targeting different antigens.

Humans↗
PubMed2001

[Growth and development of plants in a sequence of generations under the conditions of space flight (experiment Greenhouse-3)].

The purpose was to study characteristic features of growth and development of several plant generations in space flight in experiment GREENHOUSE-3 as a part of the Russian-US space research program MIR/NASA in 1997. The experiment consisted of cultivation of Brassica rapa L. in board greenhouse Svet. Two vegetative cycles were fully completed and the third vegetation was terminated on day 13 on the phase of budding. The total duration of the space experiment was 122 days, i.e. same as in the ground controls. In the experiment with Brassica rapa L. viable seeds produced by the first crop were planted in space flight and yielded next crop. Crops raised from the ground and space seeds were found to differ in height and number of buds. Both parameters were lowered in the plants grown from the space seeds. The prime course for smaller size and reduced organogenic potential of plantTs reproductive system seems to be a less content of nutrients in seeds that had matured in the space flight. Experiment GREENHOUSE-3 demonstrated principle feasibility of plant reproduction in space greenhouse from seeds developed in microgravity.

Brassica rapa↗
PubMed2005

The chemopreventive agent development research program in the Division of Cancer Prevention of the US National Cancer Institute: an overview.

Chemoprevention is an innovative area of cancer research that focuses on the development of pharmacological, biological, and nutritional interventions to prevent, reverse, or delay carcinogenesis. Over the past two decades the Division of Cancer Prevention of the US National Cancer Institute has organized a research and development program to provide resources and infrastructure to the research community for the clinical evaluation of potential cancer preventive agents. This program now encompasses preclinical agent and molecular target identification, in vitro and in vivo screening, efficacy and intermediate endpoint testing, pharmacology and toxicology assessments, and finally chemical synthesis and manufacturing leading to Investigational New Drug applications and clinical studies. In this review, examples of agents currently in development, preclinical testing models, and phase 1 and 2 clinical studies are described. Continued commitment to cancer prevention will significantly reduce the economic and medical burden of cancer.

Academies and Institutes↗
PubMed2025

Genomic determinants of antibiotic resistance for Helicobacter pylori treatment: a retrospective phenotypic and genotypic observational study.

BACKGROUND: Rising antimicrobial resistance of Helicobacter pylori is a public health challenge. Genomic-based susceptibility testing allows for the identification of resistance-associated mutations, complementing conventional diagnostics and advancing towards pathogen-based personalised therapies. Our study aimed to identify genes and mutations involved in antimicrobial resistance in H pylori and evaluate the extent to which these markers can be used as predictors of phenotypic resistance against clarithromycin and levofloxacin. METHODS: In this retrospective phenotypic and genotypic observational study, we included 1011 H pylori whole-genome sequences and strains of known geographical origin from the H pylori Genome Project (HpGP) collection. We performed phenotypic clarithromycin and levofloxacin susceptibility testing on a subset of 419 HpGP strains using Etest at a centralised laboratory. A genomic analysis was conducted to identify 23S rRNA and gyrA variants and build a curated catalogue of mutations associated with resistance to clarithromycin (ie, 23S rRNA 2142A&#x2192;G, 2142A&#x2192;C, and 2143A&#x2192;G) and levofloxacin (ie, gyrA A88V or A88P, N87K or N87I, and D91G, D91N, or D91Y). Genotype-phenotype concordance was assessed to estimate sensitivity and specificity, and the curated catalogue of resistance-associated mutations was applied to the complete HpGP set. Region-specific prevalence of resistance-associated mutations was calculated for a combined dataset including the HpGP genomes and 768 whole-genome sequences retrieved from the US National Center for Biotechnology Information Sequence Read Archive repository. Associations between resistance genotypes, H pylori subpopulations, and minimum inhibitory concentrations (MICs) were tested. FINDINGS: Clarithromycin-resistant and levofloxacin-resistant HpGP strains were estimated with a sensitivity and specificity of 100%, with all confidence intervals ranging from 96% to 100%. The combined analysis (n=1779) found the highest prevalence of clarithromycin resistance in the western Pacific region (173 [51&#xb7;2%] of 338 in southeast Asia and 75 [29&#xb7;8%] of 252 in eastern Asia), north African region (seven [38&#xb7;9%] of 18), and western Asian region (12 [31&#xb7;6%] of 38), whereas the highest prevalence of levofloxacin resistance was found in south Asia (14 [51&#xb7;85%] of 27), Central America (48 [38&#xb7;7%] of 124), eastern Europe (four [36&#xb7;4%] of 11), and southern Africa (three [33&#xb7;3%] of nine). Similarly, 23S rRNA and gyrA genotypes are variable across H pylori subpopulations. MIC values changed depending on the specific mutation in 23S rRNA (mean clarithromycin MIC 24&#xb7;61 mg/L [95% CI 12&#xb7;27-36&#xb7;96] for 2143A&#x2192;G and 142&#xb7;25 mg/L [95% CI 77&#xb7;88-206&#xb7;61] for 2142A&#x2192;G) and gyrA (mean levofloxacin MIC 9&#xb7;66 mg/L [95% CI 6&#xb7;75-12&#xb7;56] for mutations on codon 91, and 27&#xb7;97 mg/L [95% CI 25&#xb7;82-30&#xb7;11] for mutations on codon 87). INTERPRETATION: Mutations in specific genes are reliable indicators to clarithromycin and levofloxacin resistance in H pylori, making them useful markers for the development of diagnostic assays and molecular monitoring. Our results suggest that using clarithromycin and levofloxacin empirically, without previous susceptibility testing, is unsuitable in all geographical regions covered by this study. FUNDING: Intramural Research Program of the US National Cancer Institute, the European Research Council, and the Spanish Ministry of Science and Innovation.

Helicobacter pylori↗
PubMed2000

The optimal number of fathers. Evolution, demography, and history in the shaping of female mate preferences.

Around the world polygynous marriage (one man, several women) is vastly more common than polyandrous marriage (one woman, several men), and women tend to be more cautious about entering into sexual relationships than men are. Such patterns are often assumed to reflect essential differences between the sexes. However, the same dichotomy between "ardent" males and "coy" females is not found in other primates. Furthermore, under a range of circumstances females enhance their reproductive success by mating with multiple partners and use polyandrous mating (soliciting copulations from several or more males) to circumvent male-imposed costs on their free choice of mates. The existence of one-male mating systems does not prove that females "naturally" gravitate to them. Typically monandrous (copulating with just one partner) mating systems are maintained by one male excluding rivals or by other circumstances that distort female options. As with many other animals, primate females (including women) can benefit reproductively from polyandrous matings. Understanding this takes us beyond narrow research programs intent on demonstrating "universal" differences between the sexes, and allows us to study females as flexible and opportunistic individuals who confront recurring reproductive dilemmas and tradeoffs within a world of shifting options.

Biological Evolution↗
PubMed1992

Poland-US collaborative study on cardiovascular epidemiology: classification agreement between US National Cholesterol Education Program and European Atherosclerosis Society hyperlipidemia guidelines in selected Polish and US populations.

Data from two epidemiological studies are used to measure the degree to which two well-known guidelines agree in measuring hyperlipidemia in population samples in the US and Poland. The epidemiological studies are the US Lipid Research Clinics Program Prevalence Study and the Pol-MONICA project in Poland and the guidelines are those adopted by the US National Cholesterol Program (USNCEP) and by the European Atherosclerosis Society (EAS). EAS guidelines were analyzed in two ways: Method 1 used triglycerides and total cholesterol only in classifying persons as hyperlipidemics or non-hyperlipidemics; Method 2 used triglycerides, total cholesterol and nine additional risk factors in the classification process. USNCEP guidelines used total cholesterol, low density lipoprotein cholesterol and the same additional nine risk factors used in EAS Method 2 in classifying hyperlipidemics. Classification differences between the two sets of guidelines were high when EAS Method 1 guidelines were compared with USNCEP guidelines. However, EAS Method 2 which included risk factors, compared favorably with USNCEP guidelines in all three populations under study.

Adult↗
PubMed1980

Cognition and behaviour change.

For the past decade we have been attempting to understand the role of cognition in psychopathology and behaviour modification. The purpose of the present paper is to highlight and discuss what we consider to be some of the most important findings and issues that have emerged. While many other investigators are conducting related research, we have limited our review and discussion to work conducted by Meichenbaum and his colleagues. The research program and the field in general have been reviewed in more detail by Meichenbaum (1977). See an annual newsletter on cognitive-behaviour modificaiton for further detailed reviews (Meichenbaum, 1975-1979). Initially, we were interested in developing and evaluating treatment procedures that blended cognitive and behavioural components. While this work continued, we have become interested in attempting to formulate an integrative model of behaviour change (Meichenbaum, 1977). The following review and discussion will describe the research program that led us to highlight the role of cognition in behaviour change.

Adaptation, Psychological↗