Publications

BACKGROUND

Human immunodeficiency virus (HIV) infection causes neurocognitive or motor function deficits in children with advanced disease, but it is unclear whether children with CD4 cell measures above the World Health Organization (WHO) thresholds for antiretroviral therapy (ART) initiation suffer significant impairment.

METHODS

The neurocognitive and motor functions of HIV-infected ART-naive Ugandan children aged 6-12 years with CD4 cell counts of >350 cells/μL and CD4 cell percentage of >15% were compared with those of HIV-uninfected children, using the Test of Variables of Attention (TOVA), the Kaufman Assessment Battery for Children, second edition (KABC-2), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2).

RESULTS

Ninety-three HIV-infected children (median CD4 cell count, 655 cells/μL; plasma HIV RNA level, 4.7 log(10) copies/mL) were compared to 106 HIV-uninfected children. HIV-infected children performed worse on TOVA visual reaction times (multivariate analysis of covariance; P = .006); KABC-2 sequential processing (P = .005), simultaneous processing (P = .039), planning/reasoning (P = .023), and global performance (P = .024); and BOT-2 total motor proficiency (P = .003). High plasma HIV RNA level was associated with worse performance in 10 cognitive measures and 3 motor measures. In analysis of only WHO clinical stage 1 or 2 HIV-infected children (n = 68), significant differences between the HIV-infected and HIV-uninfected groups (P < .05) remained for KABC-2 sequential processing, KABC-2 planning/reasoning, and BOT-2 motor proficiency.

CONCLUSIONS

Significant motor and cognitive deficits were found in HIV-infected ART-naive Ugandan children with CD4 cell counts of ∼350 cells/μL and percentages of >15%. Study of whether early initiation of ART could prevent or reverse such deficits is needed.

Individuals with multimorbidity may be at increased risk of hospitalization and death. Comorbidity indexes do not capture severity of illness or healthcare utilization; however, inflammation biomarkers that are not disease-specific may predict hospitalization and death in older adults. We sought to predict hospitalization and mortality of older adults using inflammation biomarkers. From a prospective, observational study, 370 community-dwelling adults 65 years or older from central Alabama participated in an in-home assessment and provided fasting blood samples for inflammation biomarker testing in 2004. We calculated an inflammation summary score (range 0-4), one point each for low albumin, high C-reactive protein, low cholesterol, and high interleukin-6. Utilizing Cox proportional hazards models, inflammation summary scores were used to predicted time to hospitalization and death during a 4-year follow up period. The mean age was 73.7 (±5.9 yrs), and 53 (14%) participants had summary scores of 3 or 4. The rates of dying were significantly increased for participants with inflammation summary scores of 2, 3, or 4 (hazard ratio (HR) 2.22, 2.78, and 7.55, respectively; p<0.05). An inflammation summary score of 4 significantly predicted hospitalization (HR 5.92, p<0.05). Community-dwelling older adults with biomarkers positive for inflammation had increased rates of being hospitalized or dying during the follow up period. Assessment of the individual contribution of particular inflammation biomarkers in the prediction of health outcomes in older populations and the development of validated summary scores to predict morbidity and mortality are needed.

Since the 1989 discovery that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), there has been substantial progress toward understanding the molecular basis for CF lung disease, leading to the discovery and development of new therapeutic approaches. However, the earliest impact of the loss of CFTR function on airway physiology and structure and its relationship to initial infection and inflammation are poorly understood. Universal newborn screening for CF in the United States represents an unprecedented opportunity for investigating CF clinical manifestations very early in life. Recently developed animal models with pulmonary phenotypic manifestations also provide a window into the early consequences of this genetic disorder. For these reasons, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of extramural experts, entitled "Future Research Directions in Early CF Lung Disease" on September 21-22, 2010, to identify future research directions of great promise in CF. The priority areas identified included (1) exploring pathogenic mechanisms of early CF lung disease; (2) leveraging newborn screening to elucidate the natural history of early lung disease; (3) developing a spectrum of biomarkers of early lung disease that reflects CF pathophysiology, clinical outcome, and response to treatment; (4) exploring the role of genetics/genomics (e.g., modifier genes, gene-environmental interactions, and epigenetics) in early CF pathogenesis; (5) defining early microbiological events in CF lung disease; and (6) elucidating the initial airway inflammatory, remodeling, and repair mechanisms in CF lung disease.

Although clinic-based cohorts are most representative of the "real world," they are susceptible to loss to follow-up. Strategies for managing the impact of loss to follow-up are therefore needed to maximize the value of studies conducted in these cohorts. The authors evaluated adult patients starting antiretroviral therapy at an HIV/AIDS clinic in Uganda, where 29% of patients were lost to follow-up after 2 years (January 1, 2004-September 30, 2007). Unweighted, inverse probability of censoring weighted (IPCW), and sampling-based approaches (using supplemental data from a sample of lost patients subsequently tracked in the community) were used to identify the predictive value of sex on mortality. Directed acyclic graphs (DAGs) were used to explore the structural basis for bias in each approach. Among 3,628 patients, unweighted and IPCW analyses found men to have higher mortality than women, whereas the sampling-based approach did not. DAGs encoding knowledge about the data-generating process, including the fact that death is a cause of being classified as lost to follow-up in this setting, revealed "collider" bias in the unweighted and IPCW approaches. In a clinic-based cohort in Africa, unweighted and IPCW approaches-which rely on the "missing at random" assumption-yielded biased estimates. A sampling-based approach can in general strengthen epidemiologic analyses conducted in many clinic-based cohorts, including those examining other diseases.

BACKGROUND

The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society guidelines provide patient selection criteria for primary prevention implantable cardioverter-defibrillators (ICDs). For unknown reasons, guideline-discordant practice is common.

OBJECTIVE

To determine referring physicians' concordance with the primary prevention ICD guidelines.

METHODS

We mailed a survey regarding ICD guidelines and individual practice characteristics to a random national sample of 3000 physicians selected from the American Medical Association Masterfile-one-third each specializing in family medicine, internal medicine, and general cardiology.

RESULTS

Sixty-four percent with correct contact information responded. Three hundred ninety-five (28%; 95% confidence interval [CI] 25%-30%) respondents never refer patients with the intent of consideration for a primary prevention ICD, including 7% (95% CI 5%-10%) of cardiologists. Two hundred twelve (15%; 95% CI 13%-17%) believe ventricular arrhythmias are required before a primary prevention ICD is indicated; 525 (36%; 95% CI 34%-39%) believe that an ejection fraction of >40% warrants a primary prevention ICD; and 361 (25%; 95% CI 23%-27%) would refer a patient for a primary prevention ICD within 40 days of a myocardial infarction. In multivariate analyses, family practice physicians and physicians residing in the western United States most often provided guideline-discordant answers, while cardiologists and those who refer to an electrophysiologist most often provided guideline-concordant answers. Primary care physicians who manage heart failure patients without referral to a subspecialist were not more likely to provide guideline-concordant answers.

CONCLUSIONS

Answers discordant with the primary prevention ICD guidelines were common, suggesting that referring physician beliefs are an important barrier to appropriate patient referrals for primary prevention ICD implantation.

Prevention with Positives (PwP) is a component of the US HIV prevention strategy that targets HIV-infected persons who are aware of their seropositive status. This paper examines the use of prevention messages by clinical providers during the PwP intervention period of the US Health Resources and Services Administration's Special Projects of National Significance program. Quantitative approaches were used to learn which prevention topics were most discussed and qualitative interviews were also utilized to better understand the clinician perspective in providing prevention counseling. At 12-month follow-up, there was a significant increase in the percent of patients receiving all PwP counseling messages (p<0.01). Providers reported discussing safer sex with 91% of patients when sexually transmitted infection (STI) screening was conducted during a visit, an increase from baseline (83.5%). The percent of providers reporting they regularly explained the risk of superinfection to their clients also increased from 75% at baseline to 90% at 12-month follow up (p<0.001). Qualitative data suggest that providers prioritize individual care over public health approaches to PwP in counseling. Discussing superinfection offered providers a way to discuss HIV prevention from a non-judgmental clinical perspective while focusing on a patient-centered philosophy of care. However, the threat of superinfection may not be the best counseling option. Examples such as STI screening, giving messages to reduce the number of sexual partners and adherence to medication, are more evidence-based approaches to changing HIV transmission risk behavior and may be more important in PwP. Findings suggest that in order for HIV care providers to incorporate HIV prevention discussions into their practice, acceptable approaches to speaking about risk behavior and prevention of HIV transmission must be developed.