Evaluation of caffeine and taurine administration in improving neurodegenerative dysfunction in Caenorhabditis elegans overexpressing the APP ortholog: APL-1

INTRODUCTION: Alzheimer’s Disease (AD) is characterized by an over-accumulation of β-amyloid plaques and neurofibrillary Tau tangles present within the brain, contributing to associative neurodegeneration. Taurine is an essential amino acid found within the nervous system; however, it is one of a few amino acids not required in routine protein synthesis. Caffeine and taurine have both been identified as active ingredients in energy drinks with the benefit of improving nervous system function, supporting neural recovery, and synaptogenesis. In previous studies, taurine has been shown to increase memory retention in animal models, and consumption of caffeine reflects improvement in locomotion, memory, and lifespan. OBJECTIVES: This project aims to determine the impact of caffeine and taurine on a mutant C. elegans strain, ynIs-79, which over-expresses the amyloid precursor protein ortholog, APL-1 within its nervous system. We expect that supplementing the mutant ynIs-79 nematode’s diet with caffeine and/or taurine will positively influence the observed neurodegenerative dysfunction by reducing the number of taps required to induce habituation. We hypothesize that treating the nematodes with caffeine and/or taurine will result in a statistically significant decrease in the number of taps required to induce a habitual response and for the mutant nematodes to associate it as a non-harmful stimulus. This would suggest an improvement in memory and neurodegenerative dysfunction. METHODS: This was an observational study assessing the effects of caffeine and taurine administration and improvements in neurodegenerative dysfunction in a dose-dependent manner. The primary endpoint was the number of taps required to induce habituation and theoretically improve learning and movement in C. elegans. For comparison, we assessed anterior and posterior habituation following exposure to caffeine or taurine by tapping the worms with a sterile eyelash until the nematodes recognized the taps as a non-threatening stimulus. Control and mutant C. elegans were treated with 250μL of caffeine or taurine separately, at the following drug concentrations: 0μg/mL(control), 1μg/mL, 10μg/mL, 250μg/mL, and 500μg/mL. RESULTS: Thirty nematodes were tapped on the anterior and posterior ends after application of caffeine and/or taurine at varying concentrations. Current preliminary results indicate a significant decrease in the number of taps required for habituation in the mutant ynIs-79 C. elegans strain, comparatively. Statistical analysis included a one-way ANOVA and Dunnett’s multiple comparison test for repeated measures using Prism. CONCLUSION: The administration of caffeine towards mutant ynIs-79 C. elegans leads to improvements in observed neurodegenerative dysfunction at higher concentrations of caffeine by reducing the threshold required to induce habituation. However, administration of taurine does not reflect a dose-dependent reduction in the number of taps required to elicit habituation. Rather, administration of taurine at minimal concentrations is sufficient to achieve the desired effect. Repeated studies are needed to provide for targeted assessment of anterior and posterior response to tap habituation separately. Testing the same worm for both anterior and posterior response may provide for overstimulation of the nematode and reflect increased variability in the data

Acquisition of sexual orientation and gender identity data among NCI Community Oncology Research Program practice groups

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149296/1/cncr31925_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149296/2/cncr31925.pd

Determinants of variation in radical local treatment for men with high-risk localised or locally advanced prostate cancer in England.

BACKGROUND: Many factors are implicated in the potential 'under-treatment' of prostate cancer but little is known about the between-hospital variation. METHODS: The National Prostate Cancer Audit (NPCA) database was used to identify high-risk localised or locally advanced prostate cancer patients in England, between January 2014 and December 2017, and the treatments received. Hospital-level variation in radical local treatment was explored visually using funnel plots. The intra-class correlation coefficient (ICC) quantified the between-hospital variation in a random-intercept multivariable logistic regression model. RESULTS: 53,888 men, from 128 hospitals, were included and 35,034 (65.0%) received radical local treatment. The likelihood of receiving radical local treatment was increased in men who were younger (the strongest predictor), more affluent, those with fewer comorbidities, and in those with a non-Black ethnic background. There was more between-hospital variation (P < 0.001) for patients aged ≥80 years (ICC: 0.235) compared to patients aged 75-79 years (ICC: 0.070), 70-74 years (ICC: 0.041), and <70 years (ICC: 0.048). Comorbidity and socioeconomic deprivation did not influence the between-hospital variation. CONCLUSIONS: Radical local treatment of high-risk localised or locally advanced prostate cancer depended strongly on age and comorbidity, but also on socioeconomic deprivation and ethnicity, with the between-hospital variation being highest in older patients

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) has been rapidly adopted without robust evidence comparing its functional outcomes against laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (ORP) approaches. This study compared patient-reported functional outcomes following RARP, LRP or ORP. METHODS: All men diagnosed with prostate cancer in England during April - October 2014 who underwent radical prostatectomy were identified from the National Prostate Cancer Audit and mailed a questionnaire 18 months after diagnosis. Group differences in patient-reported sexual, urinary, bowel and hormonal function (EPIC-26 domain scores) and generic health-related quality of life (HRQoL; EQ-5D-5L scores), with adjustment for patient and tumour characteristics, were estimated using linear regression. RESULTS: In all, 2219 men (77.0%) responded; 1310 (59.0%) had RARP, 487 (21.9%) LRP and 422 (19.0%) ORP. RARP was associated with slightly higher adjusted mean EPIC-26 sexual function scores compared with LRP (3·5 point difference; 95% CI: 1.1-5.9, P=0.004) or ORP (4.0 point difference; 95% CI: 1.5-6.5, P=0.002), which did not meet the threshold for a minimal clinically important difference (10-12 points). There were no significant differences in other EPIC-26 domain scores or HRQoL. CONCLUSIONS: It is unlikely that the rapid adoption of RARP in the English NHS has produced substantial improvements in functional outcomes for patients

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

Infiltrating Cells and IFN␥ Production in the Injected Eye after Uniocular Anterior Chamber Inoculation of HSV-1

PURPOSE. After uniocular anterior chamber (AC) inoculation with HSV-1, the anterior segment of the injected eye becomes inflamed and infected; however, virus does not spread from the anterior segment and infect the retina of the injected eye. The purpose of this study was to identify early infiltrating cells and to determine whether infiltrating cells produce interferon (IFN)␥. METHODS. Euthymic, female, BALB/c mice were injected in one AC with 3 ϫ 10 4 PFU of HSV-1 (KOS) in a volume of 2 L. Mice from each group were killed at 12, 24, 36, 48, and 72 hours post injection (pi), the eyes were enucleated, and frozen sections were stained with antibodies specific for IFN␥, Mac-1 (CD11b), CD49b, F4/80, CD4, CD8, and CD11c. The same antibodies were also used to stain single-cell suspensions of ocular cells for flow cytometry. RESULTS. In the anterior segment of the injected eye, the ciliary body, and iris were virus infected and inflamed, and infiltrating cells increased throughout the period of observation. Mac-1 ϩ , CD49b ϩ , and F4/80 ϩ cells colocalized with IFN␥ in the anterior segment as early as 12 hours pi, and the percentage of Mac-1 ϩ cells increased in the injected eye beginning at 24 hours pi and continued to 72 hours pi. CONCLUSIONS. Taken together, these results demonstrate that Mac-1 ϩ cells are important IFN␥-producing cells in the injected eye before day 3 and suggest that the IFN␥ produced by these cells is involved in inhibition of anterior to posterior spread of virus in the injected eye. (Invest Ophthalmol Vis Sci

Management of prostate cancer in older patients: updated recommendations of a working group of the International Society of Geriatric Oncology

In 2010, the International Society of Geriatric Oncology (SIOG) developed treatment guidelines for men with prostate cancer who are older than 70 years old. In 2013, a new multidisciplinary SIOG working group was formed to update these recommendations. The consensus of the task force is that older men with prostate cancer should be managed according to their individual health status, not according to age. On the basis of a validated rapid health status screening instrument and simple assessment, the task force recommends that patients are classed into three groups for treatment: healthy or fit patients who should have the same treatment options as younger patients; vulnerable patients with reversible impairment who should receive standard treatment after medical intervention; and frail patients with non-reversible impairment who should receive adapted treatment