Center for Scientific Review

Deficiencies in methods reporting in animal experimentation lead to difficulties in reproducing experiments; the authors propose a set of reporting standards to improve scientific communication and study design. Animal studies have contributed immensely to our understanding of diseases and assist the development of new therapies, but inadequate experimental reporting can sometimes render such studies difficult to reproduce and to translate into the clinic. This year, a US National Institute of Neurological Disorders and Stroke workshop addressed this issue, and its conclusions are discussed in a Perspective piece in this issue of Nature. The main workshop recommendation is that at a minimum, studies should report on randomization, blinding, sample-size estimation and how the data were handled. The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

Peer Reviewed

Chronic obstructive pulmonary disease is a major cause of chronic morbidity and mortality throughout the world. COPD is currently the fourth leading cause of death in the world, and further increases in the prevalence and mortality of the disease can be predicted in the coming decades. A unified international effort is required to reverse these trends. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is a collaborative project of the United States NHLBI and WHO. Its goals are to increase awareness of COPD and decrease morbidity and mortality from this disease. GOLD aims to improve prevention and management of COPD through a concerted worldwide effort of people involved in all facets of health care and health care policy, and to encourage a renewed research interest in this extremely prevalent disease. The GOLD Workshop Report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, presents a COPD management plan with 4 components: (1) assess and monitor disease, (2) reduce risk factors, (3) manage stable COPD, and (4) manage exacerbations. The Workshop Report is based on the best-validated current concepts of COPD pathogenesis and the available evidence on the most appropriate management and prevention strategies. It has been developed by individuals with expertise in COPD research and patient care and extensively reviewed by many experts and scientific societies. Before its release for publication, the Workshop Report was reviewed by the NHLBI and the WHO. This Executive Summary provides key information about COPD; the full Workshop Report provides more details.

OBJECTIVE: To measure utilization of complementary and alternative medicine (CAM) by US adults. METHODS: We analyzed data from the 1999 National Health Interview Survey (NHIS), which covers the noninstitutionalized civilian US population. Information on 12 types of CAM use in the past 12 months was obtained from 30,801 respondents aged 18 years and older. Statistical analyses were performed using the SUDAAN software package to account for the complex sample design of the NHIS. RESULTS: An estimated 28.9% of US adults used at least one CAM therapy in the past year. The three most commonly used therapies were spiritual healing or prayer (13.7%), herbal medicine (9.6%), and chiropractic therapies (7.6%). The use of CAM was most prevalent among women, persons aged 35 to 54 years, and persons with an educational attainment of > or =16 years. The overall CAM use was higher for white non-Hispanic persons (30.8%) than for Hispanic (19.9%) and black non-Hispanic persons (24.1%). Although the use was higher for persons who had health insurance than for those who did not, the difference was not statistically significant after adjusting for age, gender and educational attainment. Compared with nonusers, CAM users were more likely to use conventional medical services. CONCLUSIONS: Estimates of CAM use in this nationally representative sample were considerably lower than have been reported in previous surveys. Most CAM therapies are used by US adults in conjunction with conventional medical services.

BACKGROUND: Females in the United States consume less alcohol and cause and experience fewer alcohol-related harms than males. However, recent research suggests such gaps might be narrowing. The purpose of this study was to explore changes in alcohol use and associated outcomes among females and males in the United States between 2002 and 2012. METHODS: Data from the National Survey on Drug Use and Health were used to assess the prevalence and trends for females and males aged 12+ in lifetime abstinence, age of onset, current drinking, binge drinking, drinking and driving, reaching DSM-IV criteria for an alcohol use disorder, combining alcohol with other drugs such as marijuana, and other variables. Of particular interest was whether differences between females and males narrowed during the decade under study. RESULTS: Differences in the drinking patterns of females and males aged 12+ narrowed between 2002 and 2012 for current drinking, number of drinking days per month, past year DSM-IV alcohol abuse, and past-year driving under the influence of alcohol. In addition, convergence was noted in 1 or more age subgroups for the prevalence of binge drinking and DSM-IV alcohol dependence and mean age at drinking onset. Divergence in drinking habits did not occur for any measure in any age subgroups with the exception of a greater increase in the prevalence of combining alcohol with marijuana among young adult male drinkers than female drinkers aged 18 to 25. CONCLUSIONS: Between 2002 and 2012, differences in alcohol consumption and related outcomes narrowed for females and males. Reasons for converging patterns of alcohol use are unclear and do not appear to be easily explainable by recent trends in employment status, pregnancy status, or marital status. More research is needed to identify the psychosocial and environmental contributors to these changes and to assess implications for prevention and treatment efforts.

The increasing knowledge of the exact biochemical nature of the localized and systemic amyloid disorders has made a logical and easily understood nomenclature absolutely necessary. Such a nomenclature, biochemically based, has been used for several years but the current literature is still mixed up with many clinical and histochemically based designations from the time when amyloid in general was poorly understood. All amyloid types are today preferably named by their major fibril protein. This makes a simple and rational nomenclature for the increasing number of amyloid disorders known in humans and animals.

The modern nomenclature of amyloidosis now includes 25 human and 8 animal fibril proteins. To be included in the list, the protein has to be a major fibril protein in extracellular deposits, which have the characteristics of amyloid, including affinity for Congo red with resulting green birefringence. Synthetic fibrils with amyloid properties are best named 'amyloid-like'. With increasing knowledge, however, the borders between different protein aggregates tend to become less sharp.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with hypercoagulability and increased thrombotic risk in critically ill patients. To our knowledge, no studies have evaluated whether aspirin use is associated with reduced risk of mechanical ventilation, intensive care unit (ICU) admission, and in-hospital mortality. METHODS: A retrospective, observational cohort study of adult patients admitted with COVID-19 to multiple hospitals in the United States between March 2020 and July 2020 was performed. The primary outcome was the need for mechanical ventilation. Secondary outcomes were ICU admission and in-hospital mortality. Adjusted hazard ratios (HRs) for study outcomes were calculated using Cox-proportional hazards models after adjustment for the effects of demographics and comorbid conditions. RESULTS: Four hundred twelve patients were included in the study. Three hundred fourteen patients (76.3%) did not receive aspirin, while 98 patients (23.7%) received aspirin within 24 hours of admission or 7 days before admission. Aspirin use had a crude association with less mechanical ventilation (35.7% aspirin versus 48.4% nonaspirin, P = .03) and ICU admission (38.8% aspirin versus 51.0% nonaspirin, P = .04), but no crude association with in-hospital mortality (26.5% aspirin versus 23.2% nonaspirin, P = .51). After adjusting for 8 confounding variables, aspirin use was independently associated with decreased risk of mechanical ventilation (adjusted HR, 0.56, 95% confidence interval [CI], 0.37-0.85, P = .007), ICU admission (adjusted HR, 0.57, 95% CI, 0.38-0.85, P = .005), and in-hospital mortality (adjusted HR, 0.53, 95% CI, 0.31-0.90, P = .02). There were no differences in major bleeding (P = .69) or overt thrombosis (P = .82) between aspirin users and nonaspirin users. CONCLUSIONS: Aspirin use may be associated with improved outcomes in hospitalized COVID-19 patients. However, a sufficiently powered randomized controlled trial is needed to assess whether a causal relationship exists between aspirin use and reduced lung injury and mortality in COVID-19 patients.

BACKGROUND: Acute alcohol consumption and chronic alcohol consumption increase the burden placed on emergency departments (EDs) by contributing to injury and disease. Whether the prevalence of alcohol-related ED visits in the United States has changed in recent years is unknown. The purpose of this study was to examine trends in ED visits involving acute and chronic alcohol consumption in the United States by age and sex between 2006 and 2014. METHODS: Data from the Nationwide Emergency Department Sample (NEDS), the largest all-payer ED database in the United States involving 945 hospitals in 33 states and Washington, DC, were analyzed to assess changes in prevalence and rates of ED visits involving acute and chronic alcohol consumption by age and sex over time among persons aged ≥12 between 2006 and 2014. RESULTS: Between 2006 and 2014, the number of ED visits involving alcohol consumption increased 61.6%, from 3,080,214 to 4,976,136. The rate increased 47% from 1,223 to 1,802 per 100,000 population and the total cost of such visits increased 272% from $4.1 billion to $15.3 billion. The number of acute alcohol-related ED visits increased 51.5% from 1,801,006 to 2,728,313 and the rate increased 40% from 720.9 to 1,009.6 per 100,000 population. The number chronic alcohol-related visits increased 75.7% from 1,279,208 to 2,247,823 and the rate increased 57.9% from 502.2 to 792.9 per 100,000. The annual percentage change in rates of all alcohol-related ED visits was larger for females than for males (5.3% vs. 4.0%). Other drug involvement increased the likelihood of admission for inpatient treatment. CONCLUSIONS: Alcohol consumption contributed to an increasing number of ED visits in the United States between 2006 and 2014, especially among females. Increased utilization of evidence-based interventions is needed.

OBJECTIVES: Health-related quality of life measures are used to evaluate patient outcomes in clinical trials of new treatments for human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Summary index scores, rather than profiles of scale scores, would simplify data analysis and interpretation of findings from clinical trials and comparison across studies. METHODS: Baseline MOS HIV Health Survey scores from two clinical trials of new antiretroviral medications in HIV/AIDS patients (total n = 2253) and an observational study (n = 162) were used to develop physical health summary (PHS) and mental health summary (MHS) scores. Exploratory and confirmatory factor analysis were used to identify the factor structure of the summary scores based on MOS HIV Health Survey scales. Physical health summary and MHS scores were derived and the factor structure proved invariant across the two groups. RESULTS: Reliability of the PHS score was 0.90 to 0.92 and MHS score was 0.91 to 0.94. Mean PHS and MHS scores differed in patient groups defined by HIV disease stage, HIV disease severity, Karnofsky performance status scores, and global ratings of health status. Mean PHS and MHS scores in patient reporting worsening health status were significantly lower than scores of patients reporting stable or improving health status. CONCLUSIONS: The PHS and MHS were reproducible across different samples of HIV/AIDS patients and are reliable and valid measures for demonstrating treatment impact on patient functioning and well-being.

BACKGROUND: The majority of U.S. older adults consume alcoholic beverages. The older population is projected to almost double by 2050. Substantially more drinkers are likely. PURPOSE: To describe gender-specific trends (1997 to 2014) in prevalence of drinking status (lifetime abstention, former drinking, current drinking [including average volume], and binge drinking) among U.S. adults ages 60+ by age group and birth cohort. METHODS: In the 1997 to 2014 National Health Interview Surveys, 65,303 respondents ages 60+ (31,803 men, 33,500 women) were current drinkers; 6,570 men and 1,737 women were binge drinkers. Prevalence estimates and standard errors were computed by age group (60+, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80+) and birth cohort (<1925, 1925 to 1935, 1936 to 1945, 1946 to 1954). Trends were examined using joinpoint regression and described as average annual percent change (AAPC; overall change 1997 to 2014) and annual percent change (APC; in-between infection points). Primary analyses were unadjusted. All analyses (unadjusted and adjusted for demographics/lifestyle) were weighted to produce nationally representative estimates. Statistical procedures accounted for the complex survey design. RESULTS: Among men ages 60+, unadjusted prevalence of current drinking trended upward, on average, 0.7% per year (AAPC, p = 0.02); average volume and prevalence of binge drinking remained stable. Adjusted results were similar. Among women age 60+, unadjusted prevalence of current drinking trended upward, on average, 1.6% per year (AAPC, p < 0.0001), but average volume remained stable; prevalence of binge drinking increased, on average, 3.7% per year (AAPC, p < 0.0001). Adjusted results were similar. Trends varied by age group and birth cohort. Among men born 1946 to 1954, unadjusted prevalence of current drinking trended upward, on average, 2.4% per year (AAPC, p = 0.02); adjusted results were nonsignificant. CONCLUSIONS: Our finding of upward trends in drinking among adults ages 60+, particularly women, suggests the importance of public health planning to meet future needs for alcohol-related programs.

Population aging is unprecedented, without parallel in human history, and the 21st century will witness even more rapid aging than did the century just past. Improvements in public health and medicine are having a profound effect on population demographics worldwide. By 2017, there will be more people over the age of 65 than under age 5, and by 2050, two billion of the estimated nine billion people on Earth will be older than 60 (http://unfpa.org/ageingreport/). Although we can reasonably expect to live longer today than past generations did, the age-related disease burden we will have to confront has not changed. With the proportion of older people among the global population being now higher than at any time in history and still expanding, maintaining health into old age (or healthspan) has become a new and urgent frontier for modern medicine. Geroscience is a cross-disciplinary field focused on understanding the relationships between the processes of aging and age-related chronic diseases. On October 30-31, 2013, the trans-National Institutes of Health GeroScience Interest Group hosted a Summit to promote collaborations between the aging and chronic disease research communities with the goal of developing innovative strategies to improve healthspan and reduce the burden of chronic disease.

The organization and response properties of nociceptive neurons in area 1 of the primary somatosensory cortex (SI) of anesthetized monkeys were examined. The receptive fields of nociceptive neurons were classified as either wide-dynamic-range (WDR) neurons that were preferentially responsive to noxious mechanical stimulation, or nociceptive specific (NS) that were responsive to only noxious stimuli. The cortical locations and the responses of the two classes of neurons were compared. An examination of the neuronal stimulus-response functions obtained during noxious thermal stimulation of the glabrous skin of the foot or the hand indicated that WDR neurons exhibited significantly greater sensitivity to noxious thermal stimuli than did NS neurons. The receptive fields of WDR neurons were significantly larger than the receptive fields of NS neurons. Nociceptive SI neurons were somatotopically organized. Nociceptive neurons with receptive fields on the foot were located more medial in area 1 of SI than those with receptive fields on the hand. In the foot representation, the recording sites of nociceptive neurons were near the boundary between areas 3b and 1, whereas in the hand area, there was a tendency for them to be located more caudal in area 1. The majority of nociceptive neurons were located in the middle layers (III and IV) of area 1. The fact that nociceptive neurons were not evenly distributed across the layers of area 1 suggested that columns of nociceptive neurons probably do not exist in the somatosensory cortex. In electrode tracks where nociceptive neurons were found, approximately half of all subsequently isolated neurons were also classified as nociceptive. Low-threshold mechanoreceptive (LTM) neurons were intermingled with nociceptive neurons. Both WDR and NS neurons were found in close proximity to one another. In instances where the receptive field shifted, subsequently isolated cells were also classified as nociceptive. These data suggest that nociceptive neurons in area 1 of SI are organized in vertically orientated aggregations or clusters in layers III and IV.

Hatcheries support nearly all major fisheries for Pacific salmon (Oncorhynchus spp.) and steel-head (anadromous O. mykiss) in the Pacific Northwest. However, hatcheries have been a major source of controversy for over 30 years. The Hatchery Scientific Review Group (HSRG) was tasked by Congress to identify solutions to well-known problems so hatcheries could better meet their goals of supporting sustainable fisheries and assisting with the conservation of natural populations. We reviewed over 100 facilities and 200 programs and identified three principles of hatchery reform: (1) goals for each program must be explicitly stated in terms of desired benefits and purposes; (2) programs must be scientifically defensible; and (3) hatchery programs must respond adaptively to new information. We also identified several emerging issues critical to the success of hatcheries. We concluded that hatcheries must operate in new modes with increased scientific oversight and that they cannot meet their goals without healthy habitats and self-sustaining, naturally-spawning populations.

Reparative medicine is a critical frontier in biomedical and clinical research. The National Institutes of Health Bioengineering Consortium (BECON) convened a symposium titled "Reparative Medicine: Growing Tissues and Organs," which was held on June 25 and 26, 2001 in Bethesda, Maryland. The relevant realms of cells, molecular signaling, extracellular matrix, engineering design principles, vascular assembly, bioreactors, storage and translation, and host remodeling and the immune response that are essential to tissue engineering were discussed. This overview of the scientific program summarizes the plenary talks, extended poster presentations and breakout session reports with an emphasis on scientific and technical hurdles that must be overcome to achieve the promise of restoring, replacing, or enhancing tissue and organ function that tissue engineering offers.

The translation of picornavirus genomic RNAs occurs by a cap-independent mechanism that requires the formation of specific ribonucleoprotein complexes involving host cell factors and highly structured regions of picornavirus 5' noncoding regions known as internal ribosome entry sites (IRES). Although a number of cellular proteins have been shown to be involved in picornavirus RNA translation, the precise role of these factors in picornavirus internal ribosome entry is not understood. In this report, we provide evidence for the existence of distinct mechanisms for the internal initiation of translation between type I and type II picornavirus IRES elements. In vitro translation reactions were conducted in HeLa cell cytoplasmic translation extracts that were depleted of the cellular protein, poly(rC) binding protein 2 (PCBP2). Upon depletion of PCBP2, these extracts possessed a significantly diminished capacity to translate reporter RNAs containing the type I IRES elements of poliovirus, coxsackievirus, or human rhinovirus linked to luciferase; however, the addition of recombinant PCBP2 could reconstitute translation. Furthermore, RNA electrophoretic mobility-shift analysis demonstrated specific interactions between PCBP2 and both type I and type II picornavirus IRES elements; however, the translation of reporter RNAs containing the type II IRES elements of encephalomyocarditis virus and foot-and-mouth disease virus was not PCBP2 dependent. These data demonstrate that PCBP2 is essential for the internal initiation of translation on picornavirus type I IRES elements but is dispensable for translation directed by the structurally distinct type II elements.

PURPOSE: The purpose of this study was to examine relationships between sexual orientation-based discrimination and excessive alcohol use and substance use disorders and to identify how these relationships differ by sexual identity, sex, race, Hispanic origin, and education among sexual minorities. METHODS: We used logistic regression to analyze associations between discrimination and substance use measures among 1351 gay/lesbian, bisexual, or unsure adults from a nationally representative survey. Differential effects by sexual identity, sex, race, Hispanic origin, and education were assessed using interaction models followed by stratified models. RESULTS: Discrimination was associated with increased odds of the following: exceeding weekly drinking limits [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.12-2.08] among bisexuals, any substance use disorder (aOR = 2.04, 95% CI: 1.41-2.95) and nicotine use disorder (aOR = 1.52, 95% CI: 1.08-2.14) among Hispanic sexual minorities, and exceeding weekly drinking limits (aOR = 1.56, 95% CI: 1.08-2.26) among those with a high school degree or less. CONCLUSION: Sexual orientation-based discrimination was associated with select substance use outcomes, especially among bisexuals, Hispanics, and less educated sexual minority adults, highlighting potential disparities associated with experiencing discrimination.

Abstract Heterozygous brain‐derived neurotrophic factor (BDNF) (+/–) mice display abnormalities in central serotonergic neurotransmission, develop decrements in serotonergic innervation of the forebrain, and exhibit enhanced intermale aggressiveness. As disturbances of serotonin neurotransmission are implicated in alcohol abuse and aggression, we have examined in BDNF (+/–) mice alcohol drinking behavior, as well as central 5‐hydroxytryptamine (5‐HT) 1A receptor function at the level of 5‐HT 1A receptor–G protein interaction. BDNF (+/–) mice displayed increased ethanol intake in a two‐bottle choice procedure. There was no difference in the preference ratio for non‐alcoholic tastants (i.e. quinine or saccharin) between genotypes. In the brains of alcohol‐naive mice, we measured [ 35 S]GTPγS binding stimulated by the 5‐HT 1A receptor agonist (+/–)‐8‐hydroxy‐2‐dipropyl‐aminotetralin hydrobromide (8‐OH‐DPAT; 1 µ m ). In BDNF (+/–) versus wild‐type (WT) mice, 5‐HT 1A receptor‐stimulated [ 35 S]GTPγS binding was significantly attenuated in the median raphe nucleus. There was a decrease in (+/–)8‐OH‐DPAT‐stimulated [ 35 S]GTPγS binding in the dorsal raphe, which did not reach statistical significance. In the hippocampus, 5‐HT 1A receptor–stimulated [ 35 S]GTPγS binding was significantly attenuated in BDNF (+/–) mice. 5‐HT 1A receptor–stimulated [ 35 S]GTPγS binding was attenuated in the anterior cingulate cortex and lateral septum, although these reductions did not reach statistical significance. 5‐HT 1A receptor number was not different between genotypes in any area of brain examined, suggesting that 5‐HT 1A receptor function, specifically the capacity of the 5‐HT 1A receptor to activate G proteins, is attenuated in BDNF (+/–) mice.

We examined the responses of neurons in posterior parietal area 7a to salient stimuli appearing alone or within multiple-stimulus displays in monkeys trained only to maintain fixation. Discharges in a population of parietal neurons encoded the location of the salient stimulus, although the latter had no task significance for the monkey. Neuronal selectivity for the location of the salient stimulus depended solely on its intrinsic difference from the background elements in the array and not on the color of the stimulus per se. These results were similar to those reported in monkeys trained to actively locate a salient stimulus in a multiple-stimulus display. A lower percentage of neurons with significant selectivity for the salient stimulus was observed in the fixation-only animals. These neurons took longer for the selective responses to emerge and showed a lower power of discrimination. The findings suggest that the posterior parietal cortex automatically detects and encodes the location of salient stimuli even when they are unrelated to the behavioral task.

Summary We have developed two long‐oligonucleotide microarrays for the analysis of genome features in Arabidopsis thaliana , in particular for the high‐throughput identification of transcription factor‐binding sites. The first platform contains 190 000 probes representing the 2‐kb regions upstream of all annotated genes at a density of seven probes per promoter. The second platform is divided into three chips, each of over 390 000 features, and represents the entire Arabidopsis genome at a density of one probe per 90 bases. Protein–DNA complexes resulting from the formaldehyde fixation of leaves of plants 2 h after exposure to 1 m m salicylic acid (SA) were immunoprecipitated using antibodies against the TGA2 transcription factor. After reversal of the cross‐links and amplification, the resulting ChIP sample was hybridized to both platforms. High signal ratios of the ChIP sample versus raw chromatin for clusters of neighboring probes provided evidence for 51 putative binding sites for TGA2, including the only previously confirmed site in the promoter of PR‐1 (At2g14610). Enrichment of several regions was confirmed by quantitative real‐time PCR. Motif search revealed that the palindromic octamer TGACGTCA was found in 55% of the enriched regions. Interestingly, 15 of the putative binding sites for TGA2 lie outside the presumptive promoter regions. The effect of the 2‐h SA treatment on gene expression was measured using Affymetrix ATH1 arrays, and SA‐induced genes were found to be significantly over‐represented among genes neighboring putative TGA2‐binding sites.