BackgroundAntiretroviral treatment (ART) has been massively scaled up to decrease human immunodeficiency virus (HIV)–related morbidity, mortality, and HIV transmission. However, despite documented increases in ART coverage, morbidity and mortality have remained substantial. This study describes trends in the numbers and characteristics of patients with very advanced HIV disease in the Western Cape, South Africa.MethodsAnnual cross-sectional snapshots of CD4 distributions were described over 10 years, derived from a province-wide cohort of all HIV patients receiving CD4 cell count testing in the public sector. Patients with a first CD4 count <50 cells/µL in each year were characterized with respect to prior CD4 and viral load testing, ART access, and retention in ART care.ResultsPatients attending HIV care for the first time initially constituted the largest group of those with CD4 count <50 cells/µL, dropping proportionally over the decade from 60.9% to 26.7%. By contrast, the proportion who were ART experienced increased from 14.3% to 56.7%. In patients with CD4 counts <50 cells/µL in 2016, 51.8% were ART experienced, of whom 76% could be confirmed to be off ART or had recent viremia. More than half who were ART experienced with a CD4 count <50 cells/µL in 2016 were men, compared to approximately one-third of all patients on ART in the same year.ConclusionsOngoing HIV-associated morbidity now results largely from treatment-experienced patients not being in continuous care or not being fully virologically suppressed. Innovative interventions to retain ART patients in effective care are an essential priority for the ongoing HIV response.

Endocannabinoid signaling critically regulates emotional and motivational states via activation of cannabinoid receptor 1 (CB1) in the brain. The nucleus accumbens (NAc) functions to gate emotional and motivational responses. Although expression of CB1 in the NAc is low, manipulation of CB1 signaling within the NAc triggers robust emotional/motivational alterations related to drug addiction and other psychiatric disorders, and these effects cannot be exclusively attributed to CB1 located at afferents to the NAc. Rather, CB1-expressing neurons in the NAc, although sparse, appear to be critical for emotional and motivational responses. However, the cellular properties of these neurons remain largely unknown. Here, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein tdTomato (tdT). Using these mice, we demonstrated that tdTpositive neurons within the NAc were exclusively fast-spiking interneurons (FSIs). These FSIs were electrically coupled with each other, and thus may help synchronize populations/ensembles of NAc neurons. CB1-expressing FSIs also form GABAergic synapses on adjacent medium spiny neurons (MSNs), providing feed-forward inhibition of NAc output. Furthermore, the membrane excitability of tdT-positive FSIs in the NAc was up-regulated after withdrawal from cocaine exposure, an effect that might increase FSI-to-MSN inhibition. Taken together with our previous findings that the membrane excitability of NAc MSNs is decreased during cocaine withdrawal, the present findings suggest that the basal functional output of the NAc is inhibited during cocaine withdrawal by multiple mechanisms. As such, CB1-expressing FSIs are targeted by cocaine exposure to influence the overall functional output of the NAc.C annabinoid receptor type 1 (CB1) has been extensively implicated in a variety of psychological and psychiatric disorders, including drug addiction (1, 2). Recent studies suggest that CB1 within the nucleus accumbens (NAc), a key component of the brain reward circuit, plays a particularly important role in the development and maintenance of cocaine-induced behavioral alterations (3). Compared with the extensive expression of CB1 in the striatum, the mRNA and protein levels of CB1 within the NAc are sparse, leading to the notion that CB1 at afferent terminals projecting to the NAc are largely responsible for intraNAc, CB1-dependent, cocaine-induced behaviors (4-6). However, a recent study primarily targeting CB1-expressing neurons demonstrates that inhibiting the expression of CB1 within the NAc antagonizes cocaine-induced reward responses (7). This and other results (8) suggest that CB1-expressing neurons in the NAc, although sparse, are critical for cellular and behavioral alterations induced by cocaine and other drugs of abuse.To examine these putative CB1-expressing neurons within the NAc, we generated a knock-in mouse line in which CB1-expressing neurons expressed the fluorescent protein td-Tomato (tdT). Our results show that tdT-positive neurons within the N...

In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission.

Building resilience in health systems is an imperative for low- and middle- income countries. Health service managers’ ability to implement health innovations may be a key aspect of resilience in primary healthcare facilities, promoting adaptability and functionality. This study investigated health service managers’ perceptions and experiences of adopting health innovations. We aimed to identify perceptions of constraints to adoption and emergent behaviours in response to these constraints. A convenience sample of 34 facility, clinical service and sub-district level managers was invited to participate. Six did not respond and were not contactable. In-depth individual interviews in a private space at participants’ place of work were conducted with 28 participants. Interviews were audio recorded and transcribed verbatim. NVivo 11 was used to store data and facilitate framework analysis. Study participants described constraints to innovation adoption including: staff lack of understanding of potential benefits; staff personalities, attitudes and behaviours which lead to resistance to change; high workload related to resource constraints and frequent policy changes inducing resistance to change; and suboptimal communication through health system structures. Managers reported employing various strategies to mitigate these constraints. These comprised (1) technical skills including participatory management skills, communication skills, community engagement skills and programme monitoring and evaluation skills, and (2) non-technical skills including role modelling positive attitudes, understanding staff personalities, influencing perceptions of innovations, influencing organizational climate and building trusting relationships. Managers have a vital role in the embedding of service innovations into routine practice. We present a framework of technical and non-technical skills that managers need to facilitate the adoption of health innovations. Future efforts to build managers’ capacity to implement health innovations should target these competencies.

Evaluation of specific lymphocyte subsets is important in understanding the microenvironment in cancer and holds promise as a prognostic parameter in invasive breast cancer. To address this, we used digital image analysis to integrate cell abundance, distance metrics, neighbourhood relationships and sample heterogeneity into comprehensive assessment of immune infiltrates. Lymphocyte and macrophage subpopulations were