Publications

Today, the majority of phase 1 dose-escalation first-in-human studies are designed as blinded, placebo-controlled protocols. First-in-human phase 1 studies are a critical component of the drug development process, but in our opinion, the additions of blinding and placebo control to these study protocols are a matter of faith without scientific support to show that the increased complexity, time, burdensome nature and expense of such additions, plus the increase in human subjects studied, are justified and useful in the drug development process. Here, we document the prevalence of such studies, review and respond to the rationalizations for such protocols and propose that the addition of blinding and placebo control to first-in-human and many other underpowered phase 1 studies is unnecessary because these additions provide little documented benefit to the drug development process.

Key components of advance care planning (ACP) for the elderly include choosing a surrogate decision maker, identifying personal values, communicating with surrogates and clinicians, documenting wishes in advance directives, and translating values and preferences for future medical care into medical orders. ACP often involves multiple brief discussions over time. This article outlines common benefits and barriers to ACP in primary care, and provides practical approaches to integrating key ACP components into primary care for older adults. Opportunities for multidisciplinary teams to incorporate ACP into brief clinic visits are highlighted.

BACKGROUND

Differences in carcinogen exposure from different cigarette products could contribute to differences in smoking-associated cancer incidence among Chinese compared with US smokers.

METHODS

Urine concentrations of metabolites of nicotine, the tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and polycyclic aromatic hydrocarbon metabolites (PAHs) were compared in 238 Chinese and 203 US daily smokers.

RESULTS

Comparing Chinese versus US smokers, daily nicotine intake and nicotine intake per cigarette smoked were found to be similar. When normalised for cigarettes per day, urine NNAL excretion was fourfold higher in US smokers, while the excretion of urine metabolites of the PAHs fluorene, phenanthrene and pyrene metabolites was 50% to fourfold higher in Chinese smokers (all, p<0.0001). Similar results were seen when NNAL and PAHs excretion was normalised for daily nicotine intake.

CONCLUSIONS

Patterns of carcinogen exposure differ, with lower exposure to TSNA and higher exposure to PAHs in Chinese compared with US smokers. These results most likely reflect country differences in cigarette tobacco blends and manufacturing processes, as well as different environmental exposures.

TRIAL REGISTRATION NUMBER

NCT00264342.

BACKGROUND

Anaemia is frequently associated with both HIV-infection and HIV-related tuberculosis (TB) in antiretroviral therapy (ART)-naïve patients in sub-Saharan Africa and is strongly associated with poor prognosis. However, the effect of ART on the resolution of anaemia in patient cohorts with a high prevalence and incidence of tuberculosis is incompletely defined and the impact of TB episodes on haemoglobin recovery has not previously been reported. We therefore examined these issues using data from a well-characterised cohort of patients initiating ART in South Africa.

METHODS

Prospectively collected clinical and haematological data were retrospectively analysed from patients receiving ART in a South African township ART service. TB diagnoses and time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded. Anaemia severity was classified according to WHO criteria. Multivariable logistic regression analysis was used to determine factors independently associated with anaemia after 12 months of ART.

RESULTS

Of 1,140 patients with baseline haemoglobin levels, 814 were alive in care and had repeat values available after 12 months of ART. The majority of patients were female (73%), the median CD4 count was 104 cells/uL and 30.5% had a TB diagnosis in the first year of ART. At baseline, anaemia (any severity) was present in 574 (70.5%) patients and was moderate/severe in 346 (42.5%). After 12 months of ART, 218 (26.8%) patients had anaemia of any severity and just 67 (8.2%) patients had moderate/severe anaemia. Independent predictors of anaemia after 12 months of ART included greater severity of anaemia at baseline, time-updated erythrocyte microcytosis and receipt of an AZT-containing regimen. In contrast, prevalent and/or incident TB, gender and baseline and time-updated CD4 cell count and viral load measurements were not independent predictors.

CONCLUSIONS

Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions. However, approximately one-quarter of patients remained anaemic after one year of ART and may require additional investigations and/or interventions.

Sleep disturbance has been associated with inflammation and cytokine activity, and we previously described genetic associations between cytokine polymorphisms and sleep maintenance and duration among adults with HIV/AIDS. Although sleep onset insomnia (SOI) is also a commonly reported sleep problem, associations between cytokine biomarkers and SOI have not been adequately studied. The purpose of this study was to describe SOI in relation to cytokine plasma concentrations and gene polymorphisms in a convenience sample of 307 adults (212 men, 72 women, and 23 transgender) living with HIV/AIDS. Based on the Pittsburgh Sleep Quality Index item that asks the time it usually took to fall asleep in the past month, participants were categorized as either >30min to fall asleep (n=70, 23%) or 30min or less to fall asleep (n=237). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. After adjusting for genomic estimates of ancestry, self-reported race/ethnicity and viral load, SOI was associated with higher IL-13 plasma levels and with six single nucleotide polymorphisms (SNPs): IL1B rs1143642 and rs1143623, IL6 rs4719714, IL13 rs1295686, NFKB1 rs4648110, and TNFA rs2857602. In addition, the IL1B rs1143642 polymorphism was associated with plasma levels of IL-1β in adjusted analyses. This study strengthens the evidence for an association between inflammation and sleep disturbance, particularly self-report of habitual SOI. In this chronic illness population, the cytokine polymorphisms associated with SOI provide direction for future personalized medicine intervention research.