Publications

BACKGROUND

HIV-infected women risk sexual and perinatal HIV transmission during conception, pregnancy, childbirth, and breastfeeding. We compared HIV-1 RNA suppression and medication adherence across periconception, pregnancy, and postpartum periods, among women on antiretroviral therapy (ART) in Uganda.

METHODS

We analyzed data from women in a prospective cohort study, aged 18-49 years, enrolled at ART initiation and with ≥1 pregnancy between 2005 and 2011. Participants were seen quarterly. The primary exposure of interest was pregnancy period, including periconception (3 quarters before pregnancy), pregnancy, postpartum (6 months after pregnancy outcome), or nonpregnancy related. Regression models using generalized estimating equations compared the likelihood of HIV-1 RNA ≤400 copies per milliliter, <80% average adherence based on electronic pill caps (medication event monitoring system), and likelihood of 72-hour medication gaps across each period.

RESULTS

One hundred eleven women contributed 486 person-years of follow-up. Viral suppression was present at 89% of nonpregnancy, 97% of periconception, 93% of pregnancy, and 89% of postpartum visits, and was more likely during periconception (adjusted odds ratio, 2.15) compared with nonpregnant periods. Average ART adherence was 90% [interquartile range (IQR), 70%-98%], 93% (IQR, 82%-98%), 92% (IQR, 72%-98%), and 88% (IQR, 63%-97%) during nonpregnant, periconception, pregnant, and postpartum periods, respectively. Average adherence <80% was less likely during periconception (adjusted odds ratio, 0.68), and 72-hour gaps per 90 days were less frequent during periconception (adjusted relative risk, 0.72) and more frequent during postpartum (adjusted relative risk, 1.40).

CONCLUSIONS

Women with pregnancy were virologically suppressed at most visits, with an increased likelihood of suppression and high adherence during periconception follow-up. Increased frequency of 72-hour gaps suggests a need for increased adherence support during postpartum periods.

Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.

Many organizations are developing health care price information tools for consumers. However, consumers may avoid low-price care if they perceive price to be associated with quality. We conducted a nationally representative survey to examine whether consumers perceive that price and quality are associated and whether the way in which questions are framed affects consumers' responses. Most Americans (58-71 percent, depending on question framing) did not think that price and quality are associated, but a substantial minority did perceive an association (21-24 percent) or were unsure whether there was one (8-16 percent). Responses to questions framed in terms of high price and high quality differed from responses to questions framed in terms of low price and low quality. People who had compared prices were more likely than those who had not compared prices to perceive that price and quality were associated. We explore implications of these findings, including how behavioral economics can inform approaches to helping consumers use price and quality information.

CONTEXT

Age-related hearing loss can impair patient-provider communication about symptom management, goals of care, and end-of-life decision-making.

OBJECTIVES

To determine whether hospice and palliative care providers screen for or received training about hearing loss, believe it impacts patient care, and use strategies to optimize communication.

METHODS

This was a national survey of hospice and palliative care providers conducted via email and social media. Survey questions were pilot tested with multidisciplinary providers in San Francisco.

RESULTS

Of 510 responses (55% age 50+ years, 65% female, 64% in practice 5+ years, 57% practiced hospital-based palliative care, 45% hospice), 315 were physicians, 50 nurses, 48 nurse practitioners, 58 social workers, and 39 chaplains. Ninety-one percent reported that hearing loss has some or great impact on the quality of care for older adults. Eighty-eight percent recalled a situation where hearing loss created a communication problem with a patient and 56% a communication problem with a caregiver. Eighty-seven percent of physicians, nurses, and nurse practitioners reported not screening for hearing loss. Although 61% felt comfortable with their communication skills for patients with hearing loss, only 21% reported having received formal training in its management, 31% were unfamiliar with resources for patients with hearing loss, and 38% had never heard of a pocket talker amplification device.

CONCLUSION

Hospice and palliative medicine providers believe age-related hearing loss impacts care yet most do not screen. Although they feel they are managing well, few have formal training. Knowledge about management approaches and resources is suboptimal.

PURPOSE OF REVIEW

First, to review how the global rise in prevalence of asthma prompted studies of the relationships between microbial exposure in early infancy, the rate and pattern of development of immune function, and the development of allergic sensitization and of wheezing in childhood. And, second, to review how those studies laid the groundwork for a possible strategy for primary prevention of asthma through manipulation of the microbiome of the gastrointestinal and/or respiratory tracts.

RECENT FINDINGS

Atopy and asthma are complex diseases thought to result from a 'gene-by-environment' interaction; the rapidity of their rise in prevalence points to a change in environment as most likely causal. Epidemiologic studies noting associations between events in infancy and later development of atopic diseases have suggested that their rise in prevalence is related to a deficiency in microbial exposure in early life. The findings from birth cohort studies of humans and from interventional studies of mice converge in suggesting that a deficiency in microbial colonization of the respiratory or gastrointestinal tract by certain commensal microbes results in skewed development of systemic and/or local immune function that increases susceptibility to allergic sensitization and to viral lower respiratory infection. Recent studies are now honing in on identifying the microbes, or collection of microbes, whose collective functions are necessary for induction of immune tolerance, and thus of reduced susceptibility.

SUMMARY

Atopy and asthma appear to have their roots in an insufficiency of early-life exposure to the diverse environmental microbiota necessary to ensure colonization of the gastrointestinal and/or respiratory tracts with the commensal microbes necessary for induction of balanced, toleragenic immune function. Identification of the commensal bacteria necessary, now ever closer at hand, will lay the groundwork for the development of strategies for primary prevention of atopic disease, especially of childhood asthma.

The COP9-Signalosome (CSN) regulates cullin-RING ubiquitin ligase (CRL) activity and assembly by cleaving Nedd8 from cullins. Free CSN is autoinhibited, and it remains unclear how it becomes activated. We combine structural and kinetic analyses to identify mechanisms that contribute to CSN activation and Nedd8 deconjugation. Both CSN and neddylated substrate undergo large conformational changes upon binding, with important roles played by the N-terminal domains of Csn2 and Csn4 and the RING domain of Rbx1 in enabling formation of a high affinity, fully active complex. The RING domain is crucial for deneddylation, and works in part through conformational changes involving insert-2 of Csn6. Nedd8 deconjugation and re-engagement of the active site zinc by the autoinhibitory Csn5 glutamate-104 diminish affinity for Cul1/Rbx1 by ~100-fold, resulting in its rapid ejection from the active site. Together, these mechanisms enable a dynamic deneddylation-disassembly cycle that promotes rapid remodeling of the cellular CRL network.

BACKGROUND

Elevated immune monitoring (IM), as measured by adenosine triphosphate (ATP) release from activated lymphocytes, has been suggested to represent an under-immunosuppressed state. Its association with the development of angiographic cardiac allograft vasculopathy (CAV) is unknown.

METHODS

Patients transplanted between January 2007 and December 2011 with annual angiograms and at least 1 IM assay were included in the analysis. Peak IM scores were determined for each patient. Patients with peak IM in the highest quartile (Group 2) were compared with those with scores in the lower quartiles (Group 1). Mild disease was scored as Grade 1 (CAV1) and moderate or severe disease was scored as Grades 2 or 3 (CAV2/3).

RESULTS

Two hundred forty patients were included. The mean age at transplant was 54.2 ± 12.1 years. Time to peak IM assay was 105.9 ± 44.1 days and average number of assays obtained per patient was 3.1 ± 1.8. Patients in the highest quartile (Group 2) had peak IM ≥446 ng ATP/ml. Mean clinical follow-up was 4.6 ± 1.7 years. CAV1 was observed in 86 of 180 (47.8%) patients in Group 1 and 39 of 60 (65.0%) in Group 2. Freedom from CAV1 was significantly lower in patients in Group 2 (log rank, p = 0.012). CAV2/3 occurred in 7 of 180 (3.7%) patients in Group 1 and 9 of 60 (15.0%) patients in Group 2. Freedom from CAV2/3 was significantly lower in patients in Group 2 (p = 0.003). In multivariate analysis elevated peak IM assay was still found to be associated with angiographic CAV (hazard ratio 1.647, confidence interval 1.020 to 2.661, p = 0.041).

CONCLUSION

Elevated peak IM, as measured by increased ATP production, in activated lymphocytes is associated with decreased freedom from angiographic CAV.

Precise genome-editing relies on the repair of sequence-specific nuclease-induced DNA nicking or double-strand breaks (DSBs) by homology-directed repair (HDR). However, nonhomologous end-joining (NHEJ), an error-prone repair, acts concurrently, reducing the rate of high-fidelity edits. The identification of genome-editing conditions that favor HDR over NHEJ has been hindered by the lack of a simple method to measure HDR and NHEJ directly and simultaneously at endogenous loci. To overcome this challenge, we developed a novel, rapid, digital PCR-based assay that can simultaneously detect one HDR or NHEJ event out of 1,000 copies of the genome. Using this assay, we systematically monitored genome-editing outcomes of CRISPR-associated protein 9 (Cas9), Cas9 nickases, catalytically dead Cas9 fused to FokI, and transcription activator-like effector nuclease at three disease-associated endogenous gene loci in HEK293T cells, HeLa cells, and human induced pluripotent stem cells. Although it is widely thought that NHEJ generally occurs more often than HDR, we found that more HDR than NHEJ was induced under multiple conditions. Surprisingly, the HDR/NHEJ ratios were highly dependent on gene locus, nuclease platform, and cell type. The new assay system, and our findings based on it, will enable mechanistic studies of genome-editing and help improve genome-editing technology.