HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ß-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation.

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of ß-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced ß-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders.

Surgical treatment of benign prostatic hyperplasia: Thulium enucleation versus single-port transvesical robotic simple prostatectomy.

Objective: The objective of this work is to compare our outcomes using thulium laser enucleation of prostate (ThuLEP) to the single-port robot-assisted simple prostatectomy (SP RASP) in the surgical management of benign prostatic hyperplasia (BPH). Methods: A retrospective cohort study was conducted from January 2017 through December 2021 of men who underwent SP RASP and ThuLEP performed by a single surgeon with an enucleation experience of >300 cases and extensive robotic experience. The primary outcome was changed in International Prostate Symptom Score (IPSS) postoperatively. Secondary outcomes were operative time, length of stay (LOS), change in post-void residuals (PVR), de novo stress- or urge-urinary incontinence (SUI, UUI), and rate of complications. Results: One hundred two patients underwent surgery during the study period: 33 RASP and 69 ThuLEP. There was no difference in preoperative characteristics, including age and body mass index, between both groups. Changes in IPSS scores postoperatively were not significant between SP RASP versus ThuLEP (-17 vs. -14, p = 0.2956). SP RASP had a longer operative time (180 vs. 90 min, p < 0.0001). There was no difference in LOS (0 vs. 0 days, p = 0.2904). There was no difference in change in PVR (-96 vs. -91 mL, p = 0.8504). SP RASP patients had significantly less postoperative SUI than ThuLEP (0 vs. 13 patients, p = 0.0083), while there was no difference in UUI between both groups (4 vs. 2 patients, p = 0.0843). There was no difference in 30-day complication rate (21.2% vs. 21.7%, p = 0.9517), although there were three ThuLEP patients with Clavien-Dindo Class III or higher complication. Conclusions: There was no difference in change in IPSS scores between the two groups. ThuLEP is associated with shorter postoperative catheter days and decreased operative times. Hospital LOS was equivalent. SP RASP demonstrates significantly improved continence rates. Though SP RASP is within the initial learning curve at our institution, early results demonstrate the role for this modality alongside ThuLEP in the treatment of large gland BPH.

'The disease isn't listening to the drug': The socio-cultural context of antibiotic use for viral respiratory infections in rural Uganda.

To identify factors precipitating antibiotic misuse and discuss how to promote safe antibiotics use and curb antibiotic resistance. Antibiotic misuse is a significant problem globally, leading to increased antibiotic resistance. Many socio-cultural factors facilitate antibiotic misuse: patient and provider beliefs about antibiotics, inadequate regulation, poor health literacy, inadequate healthcare provider training, and sub-optimal diagnostic capability. This study investigates the influence of such factors on antibiotic use and community health in rural Uganda. Attention was paid to patient-provider dynamics, providers' concerns, and the role of drug shops in the communities and how these situations exacerbate antibiotic misuse. Using a grounded ethnographic approach, interviews, focus groups, and observations were conducted over six weeks. Five salient themes emerged from data analysis. Based on the study results and a review of past literature on antibiotic resistance, there is need for improved health literacy and education, continued focus on efficiency and affordability in healthcare, and recognition of the role of stewardship and government in providing better healthcare. The problem of antibiotic misuse is multifactorial. Proposed solutions must target multiple contributing factors and must ultimately modify the culture and beliefs surrounding antibiotic use and encourage proper use. Such a multi-pronged approach would be most effective and would decrease rates of antibiotic resistance.