Do interventions to improve adherence to antiretroviral therapy recognise diversity? A systematic review

People living with HIV (PLWH) are often culturally and linguistically diverse populations; these differences are associated with differing barriers to antiretroviral therapy (ART) adherence. Cultural competence measures the extent to which trial design recognises this diversity. This systematic review aimed to determine whether adherence trial participants represent the diversity of PLWH. Randomised Controlled Trials in Organisation for Economic Co-operation and Development countries to improve ART adherence were eligible. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. For all included trials, we searched for their development, testing and evaluation studies. We compared trial participant characteristics with nationally reported PLWH data. We appraised trial cultural competence against ten criteria; scoring each criterion as 0, 1 or 2 indicating cultural blindness, pre-competence or competence respectively. For 80 included trials, a further 13 studies presenting development/testing/evaluation data for the included trials were identified. Only one of the 80 included studies reported trial participants representative of the country's population of PLWH. The median (IQ) cultural competence score was 2.5 (1.0, 4.0) out of 20. HIV adherence trial participants are not reflective of the population with HIV, which may be due to limited adoption of culturally competent research methods

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Polymer Coatings in 3D-Printed Fluidic Device Channels for Improved Cellular Adherence Prior to Electrical Lysis

This paper describes the design and fabrication of a polyjet-based three-dimensional (3D)-printed fluidic device where poly­(dimethylsiloxane) (PDMS) or polystyrene (PS) were used to coat the sides of a fluidic channel within the device to promote adhesion of an immobilized cell layer. The device was designed using computer-aided design software and converted into an .STL file prior to printing. The rigid, transparent material used in the printing process provides an optically transparent path to visualize endothelial cell adherence and supports integration of removable electrodes for electrical cell lysis in a specified portion of the channel (1 mm width × 0.8 mm height × 2 mm length). Through manipulation of channel geometry, a low-voltage power source (500 V max) was used to selectively lyse adhered endothelial cells in a tapered region of the channel. Cell viability was maintained on the device over a 5 day period (98% viable), though cell coverage decreased after day 4 with static media delivery. Optimal lysis potentials were obtained for the two fabricated device geometries, and selective cell clearance was achieved with cell lysis efficiencies of 94 and 96%. The bottleneck of unknown surface properties from proprietary resin use in fabricating 3D-printed materials is overcome through techniques to incorporate PDMS and PS

Altered Lipid Metabolism in Residual White Adipose Tissues of Bscl2 Deficient Mice

<div><p>Mutations in BSCL2 underlie human congenital generalized lipodystrophy type 2 disease. We previously reported that <i>Bscl2</i><b>^−/−</b> mice develop lipodystrophy of white adipose tissue (WAT) due to unbridled lipolysis. The residual epididymal WAT (EWAT) displays a browning phenotype with much smaller lipid droplets (LD) and higher expression of brown adipose tissue marker proteins. Here we used targeted lipidomics and gene expression profiling to analyze lipid profiles as well as genes involved in lipid metabolism in WAT of wild-type and <i>Bscl2^−/−</i> mice. Analysis of total saponified fatty acids revealed that the residual EWAT of <i>Bscl2^−/−</i> mice contained a much higher proportion of oleic_18:1n9 acid concomitant with a lower proportion of palmitic_16:0 acid, as well as increased n3- polyunsaturated fatty acids (PUFA) remodeling. The acyl chains in major species of triacylglyceride (TG) and diacylglyceride (DG) in the residual EWAT of <i>Bscl2^−/−</i> mice were also enriched with dietary fatty acids. These changes could be reflected by upregulation of several fatty acid elongases and desaturases. Meanwhile, <i>Bscl2^−/−</i> adipocytes from EWAT had increased gene expression in lipid uptake and TG synthesis but not de novo lipogenesis. Both mitochondria and peroxisomal β-oxidation genes were also markedly increased in <i>Bscl2^−/−</i> adipocytes, highlighting that these machineries were accelerated to shunt the lipolysis liberated fatty acids through uncoupling to dissipate energy. The residual subcutaneous white adipose tissue (ScWAT) was not browning but displays similar changes in lipid metabolism. Overall, our data emphasize that, other than being essential for adipocyte differentiation, Bscl2 is also important in fatty acid remodeling and energy homeostasis.</p></div

The residual <i>Bscl2</i><i>⁻</i>^{<i>/</i><i>−</i>} subcutaneous white adipose tissues were not browning but had similar altered lipid metabolism.

<p>qPCR analyses of BAT specific genes Ucp1 and Elovl3, lipolytic product activated transcription factor Pparα and its targeted genes Cpt1α and Acox2 (A); and genes involved in elongation, desaturation and TG synthesis (B) in isolated adipocytes from ScWAT of <i>Bscl2^+/+</i> and <i>Bscl2^−/−</i> mice. Each sample was pooled from 3-4 6-week-old nonfasting male wild-type and <i>Bscl2</i>^−/− mice (<i>n</i>  =  4–5). *: P<0.05; **: p<0.005. (C) TLC analysis of total lipids extracted from ScWAT of male non-fasting <i>Bscl2^+/+ and Bscl2^−/−</i> mice (n = 5–6). Total lipids from equal amounts of tissue for each genotype were loaded.</p

Lipidomic analysis of TGs by shotgun mass spectrometry of EWAT from <i>Bscl2^+/+</i> and <i>Bscl2^−/−</i> mice.

<p>TG species were determined using high resolution ESI-MS and confirmed via product ion scan mode CID-MS/MS and –MS³ as described in Methods (n = 3 pooled from 6 animals). Data are expressed as % total TG ion abundance in each genotype. Only the 46 TG species observed at >0.1% total TG ion abundance in <i>Bscl2^+/+</i> EWAT are listed. Data are presented as means ± SD. *: p<0.05; **: p<0.005. Arrows indicate upregulation or downregulation vs. <i>Bscl^+/+</i> EWAT.</p

De novo lipogenesis and metabolic pathways of MUFA and PUFAs.

<p>Fatty acids are synthesized through de novo lipogenesis (DNL) or converted from dietary palmitic_16:0, oleic_18:1n9, linoleic_18:2n6 and α-linolenic_18:3n3 acids to long chain unsaturated fatty acids <i>in vivo</i> by a series of elongation by elongases (Elovl) and desaturation (Δ5 desaturase (Δ5D/Fasd1), Δ6 desaturase (Δ6D/Fads2), or Δ9-desaturase (Δ9D/Scd1)). Fatty acids that accumulate in animal and human tissues are in solid boxes. Fatty acids derived from normal rodent chow diet are shaded in gray.</p

Lipidomic analysis of DGs by shotgun mass spectrometry of EWAT from <i>Bscl2^+/+</i> and <i>Bscl2^−/−</i> mice.

<p>DG species were determined using high resolution ESI-MS and confirmed via product ion scan mode CID-MS/MS as described in Methods (n = 3 pooled from 6 animals). Data are expressed as % total DG ion abundance in each genotype. Data are presented as means ± SD. *: p<0.05; **: p<0.005. Arrows indicate upregulation or downregulation vs. <i>Bscl^+/+</i> EWAT.</p

Altered fatty acid compositions suggest increased rate of fatty acid mobilization in residual <i>Bscl2^−/−</i> EWAT.

<p>A) Identification and quantification of changes in total adipose tissue saponified fatty acids by RP-HPLC. B) Ratio of oleic_18:1n9/palmitic_16:0 acids. C) End product/precursor ratio of DHA_22:6n3/α-linolenic_18:3n3 acids. D) Unsaturation index based on the number of double bonds per fatty acyl residue. n = 3 with each sample pooled from EWAT fat pads from 2 animals. *: p<0.05; **: p<0.005.</p

Enhanced expression of key enzymes responsible for elongation, desaturation, and triacylglyceride synthesis but not de novo lipogenesis in isolated <i>Bscl2</i><i>⁻</i>^{<i>/</i><i>−</i>} adipocytes.

<p>qPCR analyses of genes involved in elongation (A), desaturation (B), de novo lipogenesis (C), lipid uptake (D) as well as triacylglyceride synthesis (E). Each sample was pooled from 3 6-week-old nonfasting male wild-type and <i>Bscl2</i>^−/− mice (<i>n</i>  =  4). *: P<0.05; **: p<0.005.</p