Publications

BACKGROUND

Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.

METHODS

We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria.

RESULTS

The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events.

CONCLUSIONS

The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.).

OBJECTIVE

To determine if trauma exposure is associated with suicidal ideation in a nationally representative sample of older adults.

METHODS

This study included 3,277 participants 55 years and older involved in the Collaborate Psychiatric Epidemiology Surveys (2001-2003).

RESULTS

Of the 84.8% of older adults who were exposed to any trauma, 2.2% endorsed late-life suicidal ideation. Multivariable models fully adjusted for sociodemographics, post-traumatic stress disorder, major depressive disorder, and substance use revealed exposure to serious accidents/illness was associated with suicidal ideation (odds ratio: 2.55; 95% confidence interval: 1.16-5.59; Wald χ(2) = 5.47, df = 1, p = 0.019). Investigation of specific traumas within the category revealed that life-threatening illness was specifically associated with suicidal ideation in older adults (odds ratio: 2.12; 95% confidence interval: 1.34-3.36; Wald χ(2) = 10.33, df = 1, p = 0.001).

CONCLUSION

These findings highlight the need for monitoring of suicidal ideation among older adults who have been informed of a life-threatening illness diagnosis.

Although the replicative life cycle of HIV within CD4 T cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4 T cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis.

OBJECTIVE

To determine whether adding mindfulness-based eating and stress management practices to a diet-exercise program improves weight loss and metabolic syndrome components.

METHODS

In this study 194 adults with obesity were randomized to a 5.5-month program with or without mindfulness training and identical diet-exercise guidelines. Intention-to-treat analyses with multiple imputation were used for missing data. The primary outcome was 18-month weight change.

RESULTS

Estimated effects comparing the mindfulness to control arm favored the mindfulness arm in (a) weight loss at 12 months, -1.9 kg (95% CI: -4.5, 0.8; P = 0.17), and 18 months, -1.7 kg (95% CI: -4.7, 1.2; P = 0.24), though not statistically significant; (b) changes in fasting glucose at 12 months, -3.1 mg/dl (95% CI: -6.3, 0.1; P = 0.06), and 18 months, -4.1 mg/dl (95% CI: -7.3, -0.9; P = 0.01); and (c) changes in triglyceride/HDL ratio at 12 months, -0.57 (95% CI: -0.95, -0.18; P = 0.004), and 18 months, -0.36 (95% CI: -0.74, 0.03; P = 0.07). Estimates for other metabolic risk factors were not statistically significant, including waist circumference, blood pressure, and C-reactive protein.

CONCLUSIONS

Mindfulness enhancements to a diet-exercise program did not show substantial weight loss benefit but may promote long-term improvement in some aspects of metabolic health in obesity that requires further study.

Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

Broad-spectrum antibiotic use may adversely affect a patient's beneficial microbiome and fuel cross-species spread of drug resistance. Although alternative pathogen-specific approaches are rationally justified, a major concern for this precision medicine strategy is that co-colonizing or co-infecting opportunistic bacteria may still cause serious disease. In a mixed-pathogen lung infection model, we find that the Staphylococcus aureus virulence factor α toxin potentiates Gram-negative bacterial proliferation, systemic spread, and lethality by preventing acidification of bacteria-containing macrophage phagosomes, thereby reducing effective killing of both S. aureus and Gram-negative bacteria. Prophylaxis or early treatment with a single α toxin neutralizing monoclonal antibody prevented proliferation of co-infecting Gram-negative pathogens and lethality while also promoting S. aureus clearance. These studies suggest that some pathogen-specific, antibody-based approaches may also work to reduce infection risk in patients colonized or co-infected with S. aureus and disparate drug-resistant Gram-negative bacterial opportunists.