Publications

BACKGROUND

Darunavir is a second-generation protease-inhibitor used with ritonavir (DRV/r) and two nucleoside reverse-transcriptase inhibitors as an option in first-line antiretroviral treatment (ART).

METHODS

We systematically reviewed randomized controlled trials (RCTs) of DRV/r versus other regimens in patients initiating ART. We searched five bibliographic databases and other key resources. We had no language limitations. We assessed bias risk with the Cochrane tool and used GRADE to assess evidence quality. We report findings in terms of risk ratio (RR) with 95% confidence intervals (CI).

FINDINGS

Three RCTs met inclusion criteria. In plasma viral load suppression, DRV/r outperformed ritonavir-boosted lopinavir at 48 weeks (RR 1.13, 95% CI 1.03-1.25), 96 weeks (RR 1.11, 95% CI 1.02-1.21), and 192 weeks (RR 1.20, 95% CI 1.07-1.35). DRV/r was similar to dolutegravir at 48 weeks (RR 0.96, 95% CI 0.87-1.06) but less effective at 96 weeks (RR 0.84, 95% CI 0.75-0.93). At 96 weeks, DRV/r underperformed raltegravir (RR 0.94, 95% CI 0.88-0.99) but was similar to ritonavir-boosted atazanavir (RR 1.02, 95% CI 0.96-1.09). Overall bias risk was moderate. Evidence quality was also moderate.

INTERPRETATION

Initial ART regimens using DRV/r should be considered in future World Health Organization guidelines.

OBJECTIVE

Cochlear explantation for purely elective (e.g. psychological and emotional) reasons is not well studied. Herein, we aim to provide data and expert commentary about elective cochlear implant (CI) removal that may help to guide clinical decision-making and formulate guidelines related to CI explantation.

DATA SOURCES

We address these objectives via three approaches: case report of a patient who desired elective CI removal; review of literature and expert discussion by surgeon, audiologist, bioethicist, CI user and member of Deaf community.

REVIEW METHODS

A systematic review using three scientific online databases was performed. Included articles addressed the benefits and/or complications of cochlear implantation in young children, CI explantation with or without revision surgery and the ethical debate between the medical and Deaf communities on cochlear implantation and explantation.

CONCLUSIONS

The medical and audiological perspectives identify a host of risks related to implant removal without reimplantation, including risk from surgery, general anaesthesia, cochlear ossification and poor audiometric outcomes. The member of the deaf community and bioethicist argue that physicians need to guide the principles of beneficence, non-maleficence and patient autonomy. Taken together, patient desires should be seen as paramount, if the patient is otherwise fit for surgery and well informed.

IMPLICATIONS FOR PRACTICE

Similar to the case of device implantation, device explantation should be a multidisciplinary and collaborative decision with the patient and the family's desires at the centre. While every case is different, we offer a CI explantation discussion to assist in clinical decision-making, patient counselling and education.

The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.