Mycobacterial disease causing chylous effusions in two patients living with uncontrolled HIV.

Chylous effusions are a rare complication of disseminated non-tuberculous mycobacterial (NTM) infection. This is a case couplet reporting on the treatment challenge of chylous effusions secondary to NTM infection in two individuals living with advanced HIV. Their treatment was complicated by associated immune reconstitution inflammatory syndrome. They both required intermittent paracentesis, steroid treatment and transitioning on to fat-free diets alongside NTM treatment. Only after months of this treatment regimen was successful resolution of the associated chylous effusions achieved. Chylous effusions in immunosuppressed patients living with NTM infection are rarely reported and difficult to manage. This report discusses treatment approaches and highlights the difficulties faced by the treating team.

Comparing Prospective Incident Severe Acute Respiratory Syndrome Coronavirus 2 Infection Rates During Successive Waves of Delta and Omicron in Johannesburg, South Africa.

In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.

Retraction to: Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

[This retracts the article DOI: 10.1093/ofid/ofab358.]

Meta-analysis of Randomized Trials of Ivermectin to Treat SARS-CoV-2 Infection.

Ivermectin is an antiparasitic drug being investigated for repurposing against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ivermectin showed in vitro activity against SARS-COV-2, but only at high concentrations. This meta-analysis investigated ivermectin in 23 randomized clinical trials (3349 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv, and trial registries. The primary meta-analysis was carried out by excluding studies at a high risk of bias. Ivermectin did not show a statistically significant effect on survival (risk ratio [RR], 0.90; 95% CI, 0.57 to 1.42; P = .66) or hospitalizations (RR, 0.63; 95% CI, 0.36 to 1.11; P = .11). Ivermectin displayed a borderline significant effect on duration of hospitalization in comparison with standard of care (mean difference, -1.14 days; 95% CI, -2.27 to -0.00; P = .05). There was no significant effect of ivermectin on time to clinical recovery (mean difference, -0.57 days; 95% CI, -1.31 to 0.17; P = .13) or binary clinical recovery (RR, 1.19; 95% CI, 0.94 to 1.50; P = .15). Currently, the World Health Organization recommends the use of ivermectin only inside clinical trials. A network of large clinical trials is in progress to validate the results seen to date.

Comparing ex vivo and in vitro translocation of silver nanoparticles and ions through human nasal epithelium.

Silver nanomaterials are widely used in clinically approved devices, consumer goods, and over-the-counter nutraceutical products. Despite the increase in silver nanomaterial research, few investigations have specifically distinguished the biological effects resulting from silver nanoparticles (AgNPs) versus silver ions released from AgNPs. This is in part, due to the complex analytical methods required to characterize silver ion release from AgNPs in biological media. This study sought to analyze silver ion release from AgNPs in biological media, compare silver transport from soluble AgNO3 and AgNPs through ex vivo full thickness sinus human tissue explants and human nasal epithelium and determine fractional AgNP internalization by human nasal epithelial cells. Rapid silver ion release is observed from AgNPs in human nasal epithelial cell medium over 3 h (9.6% of total silver mass). Significantly lower translocation of AgNPs is observed through human nasal epithelial cell monolayers and ex vivo human sinus tissue explants compared to silver ion (AgNO3). AgNP internalization is directly observed in AgNP-exposed human nasal epithelial cell monolayers by live cell scanning transmission electron microscopy (STEM), providing one potential mechanism for AgNP transcytosis. However, in vitro AgNP dissolution experiments suggest that silver in human nasal epithelium is primarily silver ion. Ionic AgNO3 produces significantly higher silver translocation, supporting previous results claiming silver ion as primarily responsible for biological effects of AgNPs.

In vivo comparisons of silver nanoparticle and silver ion transport after intranasal delivery in mice.

Silver nanoparticles (AgNPs) are widely available as consumer goods, and over-the-counter or nutraceutical products used for alleged therapeutic and antibacterial properties. Among these products, AgNP topical therapy is proposed for treating patients with upper airway bacterial rhinosinusitis. While silver ion release from AgNPs in biological systems is well known, limited investigations actually characterize this silver ion release and their subsequent biological effects distinct from delivered particulate metallic silver. This is in part due to the analytical complexity and difficulty involved in distinguishing silver ion release from metallic AgNPs in biological media. Therefore, this study compared intranasal administration of AgNPs versus soluble silver ion (AgNO3) control to examine their transport and biological differences in tissues. First, we compared bactericidal activities of AgNPs and AgNO3 in those bacteria commonly associated with clinical rhinosinusitis in vitro. Next, we evaluated silver residence time in the sinus cavity after intranasal delivery of AgNPs and AgNO3 to mice, and characterized tissue distribution of silver in the sinonasal mucosal epithelium. We found that AgNPs show reduced bactericidal activity compared to AgNO3 (i.e., MBC of 15ppm compared to 5ppm), and significantly lower residence times in the sinus cavity (AgNP concentrations of 3.76ppm after 3h compared to 9ppm for AgNO3). AgNPs were not readily taken up into or through respiratory epithelium, with very low silver levels found in blood and no detectable silver measured in the olfactory bulb and brain. Results indicate that limited tissue distribution of silver detected from AgNPs is due to AgNP dissolution to silver ion. AgNPs therefore demonstrate adequate safety through limited penetration and absorption, but limited potential therapeutic efficacy as antimicrobials in nasal applications, as concentrations of silver in the sinus cavity drop below the minimum bactericidal concentration within 3h.

Live RB51 vaccine lyophilized hydrogel formulations with increased shelf life for practical ballistic delivery.

Ballistic delivery capability is essential to delivering vaccines and other therapeutics effectively to both livestock and wildlife in many global scenarios. Here, lyophilized poly(ethylene glycol) (PEG)-glycolide dimethacrylate crosslinked but degradable hydrogels were assessed as payload vehicles to protect and deliver a viable bacterial vaccine, Brucella abortus strain RB51 (RB51), ballistically using commercial thermoplastic cellulosic degradable biobullets. Degradable PEG hydrogel rods loaded with ∼10(10) live RB51 bacteria (CFUs) were fabricated using three different polymerization methods, cut into fixed-sized payload segments, and lyophilized. Resulting dense, glassy RB51 vaccine-loaded monoliths were inserted into thermoplastic biobullet 100-µL payload chambers. Viability studies of lyophilized formulations assessed as a function of time and storage temperature supported the abilities of several conditions to produce acceptable vaccine shelf-lives. Fired from specifically designed air rifles, gel-loaded biobullets exhibit down-range ballistic properties (i.e., kinetic energy, trajectory, accuracy) similar to unloaded biobullets. Delivered to bovine tissue, these hydrogels rehydrate rapidly by swelling in tissue fluids, with complete hydration observed after 5h in serum. Live RB51 vaccine exhibited excellent viability following carrier polymerization, lyophilization, and storage, at levels sufficient for vaccine dosing to wild range bison, the intended target. These data validate lyophilized degradable PEG hydrogel rods as useful drug carriers for remote delivery of both live vaccines and other therapeutics to livestock, wildlife, or other free-range targets using ballistic technologies.

In vivo human time-exposure study of orally dosed commercial silver nanoparticles.

Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receive increasing health assessment. We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content were determined. No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation. In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems are warranted to assert human toxicity thresholds. FROM THE CLINICAL EDITOR: In this study, the effects of commercially available nanoparticles were studied in healthy volunteers, concluding no detectable toxicity with the utilized comprehensive assays and tests. As the authors rightfully state, further studies are definitely warranted. Studies like this are much needed for the more widespread application of nanomedicine.