Predictive value of genomic screening: cross-sectional study of cystic fibrosis in 50,788 electronic health records.

Doubts have been raised about the value of DNA-based screening for low-prevalence monogenic conditions following reports of testing this approach using available electronic health record (EHR) as the sole phenotyping source. We hypothesized that a better model for EHR-focused examination of DNA-based screening is Cystic Fibrosis (CF) since the diagnosis is proactively sought within the healthcare system. We reviewed CFTR variants in 50,778 exomes. In 24 cases with bi-allelic pathogenic CFTR variants, there were 21 true-positives. We considered three cases "potential" false-positives due to limitations in available EHR phenotype data. This genomic screening exhibited a positive predictive value of 87.5%, negative predictive value of 99.9%, sensitivity of 95.5%, and a specificity of 99.9%. Despite EHR-based phenotyping limitations in three cases, the presence or absence of pathogenic CFTR variants has strong predictive value for CF diagnosis when EHR data is used as the sole phenotyping source. Accurate ascertainment of the predictive value of DNA-based screening requires condition-specific phenotyping beyond available EHR data.

Are physicians prepared for whole genome sequencing? a qualitative analysis.

Although the integration of whole genome sequencing (WGS) into standard medical practice is rapidly becoming feasible, physicians may be unprepared to use it. Primary care physicians (PCPs) and cardiologists enrolled in a randomized clinical trial of WGS received genomics education before completing semi-structured interviews. Themes about preparedness were identified in transcripts through team-based consensus-coding. Data from 11 PCPs and 9 cardiologists suggested that physicians enrolled in the trial primarily to prepare themselves for widespread use of WGS in the future. PCPs were concerned about their general genomic knowledge, while cardiologists were concerned about how to interpret specific types of results and secondary findings. Both cohorts anticipated preparing extensively before disclosing results to patients by using educational resources with which they were already familiar, and both cohorts anticipated making referrals to genetics specialists as needed. A lack of laboratory guidance, time pressures, and a lack of standards contributed to feeling unprepared. Physicians had specialty-specific concerns about their preparedness to use WGS. Findings identify specific policy changes that could help physicians feel more prepared, and highlight how providers of all types will need to become familiar with interpreting WGS results.

Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamide.

OBJECTIVE: Decreased plasma tryptophan in persons infected with human immunodeficiency virus (HIV) was first reported over a decade ago, and this observation has since been confirmed by many groups. Before this study, only zidovudine (an antiviral medication) had been reported to reverse plasma tryptophan depletion in HIV-infected persons. Starting with the hypothesis that HIV induces a pellagra-like state and that plasma tryptophan in HIV-infected patients is decreased as a known biochemical correlate of pellagra, we predicted that niacin therapy would reverse plasma tryptophan depletion as it does in pellagra. METHODS: After receiving approval from the institutional review board, we treated HIV-infected patients for 2 mo with high-dose niacin in the form of oral nicotinamide. RESULTS: There was an average 40% increase in plasma tryptophan (P = 0.01) in the four HIV-infected individuals who completed the 2-mo protocol. This finding was specific in that four other amino acids, which have been shown to have significant plasma concentration alterations during HIV infection (i.e., cystine, methionine, taurine, and lysine), showed no significant change with nicotinamide therapy. CONCLUSIONS: There were no adverse side effects attributable to this treatment. The effects of high-dose nicotinamide treatment on morbidity or mortality in HIV-infected persons are yet to be determined. This report marks the first successful use of a vitamin to reverse this HIV-induced metabolic abnormality.

Niacin as a potential AIDS preventive factor.

A pentad of findings consistent with niacin depletion have been described in patients with AIDS. There are also clinical and laboratory data to support the potential benefit of niacin in HIV infection. In this paper, it is hypothesized that HIV infection induces niacin depletion, and that therapeutic niacin will act as an AIDS preventive factor. While viral inhibition is incontrovertibly the primary 'AIDS preventive factor', costly antiretroviral medications are simply out of reach for the majority of the world's HIV-infected people. Along with antiviral research, investigation must go forward to look at strategies to overcome the massive metabolic disruption caused by the production of approximately one billion virus particles per day. Niacin, the same B complex vitamin found in the early part of this century to be the 'pellagra preventive factor', is proposed here as a secondary 'AIDS preventive factor' in HIV-infected persons.

Nursing research activities in New York state are alive and well: a survey of selected acute care facilities and schools of nursing.

This survey was conducted to assess the nature and extent of nursing research activities in acute care facilities and schools of nursing in New York state. A questionnaire was mailed to 269 acute care facilities and 42 schools of nursing with a response rate of 29%. Sixty-seven percent of acute facilities and 100% of schools responding reported participating in nursing research activities. Sixty-eight percent of the acute care facilities and 67% of the schools of nursing that participated in research activities reported that nursing research was included in staff job descriptions. The findings revealed that the organizational environment in schools was more supportive of research activities than in acute care facilities. Despite changes in health care, including overall downsizing and deletion of nursing research positions, acute care facilities and schools of nursing reported an increase in quality and quantity of research from 1992-1996 compared to 1988-1991.

HIV infection decreases intracellular nicotinamide adenine dinucleotide [NAD].

We report that HIV-1 infection of human cells in vitro leads to significant decreases in the intracellular concentration of NAD. This decrease varies with viral load and HIV strain. In tissue culture, cells lacking CD4 receptors or cells incubated with heat inactivated virus do not demonstrate this decrease in NAD. Nicotinamide, the amide form of the vitamin niacin, increases intracellular NAD levels in uninfected cells as expected. Our data demonstrate that nicotinamide also maintains increased intracellular NAD concentrations in HIV infected cells. We conclude that HIV induces a state of intracellular pellagra which is reversed by the administration of nicotinamide.

Nicotinamide inhibits HIV-1 in both acute and chronic in vitro infection.

HIV-1 infected patients can manifest a number of poorly understood conditions including dermatitis, dementia, and diarrhea. These conditions are in some ways suggestive of pellagra, the syndrome associated with niacin depletion. We demonstrate here that nicotinamide, the amide form of niacin, inhibits HIV-1 infection in cell culture. Neither nicotinic acid which is the alternative form of niacin, nor thiamine (another B complex vitamin), shows a similar degree of inhibition in tissue culture. This inhibition occurs in both primary cells and in established cell lines. In vitro models of acute and chronic HIV infection are demonstrated here to be inhibited by nicotinamide in a dose dependent manner when added in millimolar concentrations.